Nonalcoholic fatty liver disease vs. Differential effects of Subcutaneoue and gat on Plant-based supplement products tissue distribution and glucose uptake in type 2 diabetic subjects. Available information does not indicate that visceral adipose tissue contributes much to liver exposure of FFA Diabetes Care.

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The androgen receptor in female adipose tissue seems to have the same characteristics as that found in male adipose tissue. However, estrogen treatment down-regulates the density of this receptor, which might be a mechanism whereby estrogen protects adipose tissue from androgen effects. Estrogen by itself seems to protect postmenopausal women receiving replacement therapy from visceral fat accumulation Estrogen receptors are expressed in human adipose tissue and show a regional variation of density, but whether the quantity of these receptors is of physiological importance has not been clearly established With regard to progesterone, adipose cells seem to lack binding sites and mRNA for progesterone receptors, indicating that progesterone acts through glucocorticoid receptors GH receptors.

While it is well established that GH has specific and receptor-mediated effects in adipose tissue of experimental animals, the importance of GH receptors in human adipose tissue is not fully elucidated at present although the available data indicate a functional role. However, GH is clearly involved in the regulation of visceral fat mass in humans.

Acromegaly, a state of GH excess, is associated with decreased visceral fat while in GH deficiency there is an increase in visceral fat and in adults with GH deficiency, recombinant human GH replacement therapy results in adipose tissue redistribution from visceral to subcutaneous locations; however, the regulation of adipose tissue metabolism requires synergism with steroid hormones A direct demonstration of a regulation of the GH receptor in human fat cells has not yet been performed Thyroid hormone receptors.

Thyroid hormones have multiple catabolic effects on fat cells as a result of interactions with the adrenergic receptor signal transduction system, and most of these interactions are also present in human fat cells There are data regarding the characterization of the nuclear T 3 receptor in human fat cells Although receptor regulation has not yet been demonstrated, there is little doubt that the thyroid hormone receptors are important for the function of human adipose tissue Further, no data are available on the correlation between visceral fat mass and thyroid hormone levels.

Adenosine receptors. Adenosine behaves as a potent antilipolytic and vasodilator agent and can be considered as an autocrine regulator of both lipolysis and insulin sensitivity in human adipose tissue. Site differences in ambient adenosine concentration, perhaps controlled by blood flow, may also modulate adipose tissue metabolism 7.

Adenosine content is higher in omental than in abdominal subcutaneous adipose tissue, but the receptor-dependent inhibition of lipolysis is, as indicated before , less pronounced in the former than in the latter depot However, despite strong antilipolytic effect of adenosine analogs, human adipocytes contain few adenosine type A l receptors, regardless of the fat depot considered According to Arner , the α2-, β l -,β 2 -, and β 3 -adrenoreceptors and receptors for insulin, adenosine, and glucocorticoids, as well as for PGE 2 , a potent antilipolytic agent with high affinity receptors identified in adipocytes , have a major functional role, as shown by relevant biological receptor-mediated effects, the presence of a receptor molecule, and receptor regulation.

The receptors for GH, thyroid hormones, estrogen, and testosterone, as well as for acetylcholine and TSH, probably have an important functional role but complete evidence, indicated in the previous group of receptors, is not present so far; however, there is little doubt of a regulatory role. Genetic epidemiology: heritability and segregation analysis.

Studies performed in individuals from families of French descent living in Quebec City [Quebec Family Study QFS ] allowed the estimation of the fraction of the phenotypic variance that could be attributed to the genetic and environmental factors among the obesity phenotypes or in the distribution of the adipose tissue, taking into account the BMI and amount of subcutaneous fat by the sum of the measurement of skinfolds in six different sites , lean body mass, fat mass, percentage of fat derived from underwater weighing, and visceral fat by CT , The residual variance corresponded to environmental factors, but some factors cultural, nongenetic could be transmitted from parents to descendents and sometimes were confounded by genetic effects Segregation analysis studies have recently concluded that visceral fat is similarly influenced by a gene with a major effect in the QFS and HERITAGE families , However, after adjustment of the visceral adipose tissue for the fat mass, the effect of the gene with the major effect was not more compatible with a mendelian transmission.

These results suggested the presence of a pleiotropism: the gene with the major effect, identified by the fat mass , could similarly influence the amount of visceral fat Similar results were obtained with the same type of analysis in the HERITAGE cohort To test the hypothesis of a genetic pleiotropism, Rice et al.

The results of this study Fig. These results have confirmed the presence of a genetic pleiomorphism and suggested the presence of genes affecting simultaneously the amounts of fat mass and visceral abdominal fat.

Schematic representation of the genetic effects on total fat mass and visceral fat adjusted for the fat mass and on the co-variation between the two phenotypes Quebec Family Study, G 1 and G 2 represent the genetic effects specific for the total fat mass and visceral fat, respectively.

E 1 and E 2 represent the specific effects of the environment on total fat mass and visceral fat, respectively. G 3 and E 3 indicate the genetic and environment effects common to both phenotypes. Pérusse et al. The interactions of the effects of genotype and environment evaluated in monozygotic twins, when the energy balance is manipulated, indicated that even though there were large interindividual differences in the response to excess or negative energy balance, there was a significant within-pair resemblance in response 96 , In effect, in response to overfeeding, there was at least 3 times more variance in response between pairs than within pairs for the gains in body weight, fat mass, and fat-free mass In relation to the response to the negative energetic balance, at least 7 times more variation was observed in response between pairs than within members of the same pair of twins, with respect to the same variables This intrapair similarity in the response to either excess or deficient energy balance is also observed in relation to the abdominal visceral fat Thus, the interaction between genotype and environment is important to consider in the study of the genetics of obesity since the propensity to fat accumulation is influenced by the genetic characteristics of the subject.

Molecular genetics: association and linkage studies. Several candidate genes as well as random genetic markers were found to be associated with obesity as well as body fat and fat distribution in humans.

The current human obesity gene map, based on results from animal and human studies, indicates that all chromosomes, with the exception of the Y chromosome, include genes or loci potentially involved in the etiology of obesity Initial findings from the QFS showed that significant but marginal associations with body fat were found with LPL and the α2-subunit of the sodium-potassium ATPase genes The Trp64Arg mutation of the β 3 -adrenergic receptor gene β 3 AR , prevalent in some ethnic groups, is associated with visceral obesity and insulin resistance in Finns as well as increased capacity to gain weight This mutation was also shown to be associated with abdominal visceral obesity in Japanese subjects, with lower triglycerides in the Trp64Arg homozygotes but not heterozygotes It has been suggested that those with the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue.

On the other hand, Vohl et al. Previously, it was reported by the same group that apo-B gene Eco R-1 polymorphism appeared to modulate the magnitude of the dyslipidemia generally found in the insulin-resistant state linked with visceral obesity These studies are a demonstration of a significant interaction between visceral obesity and a polymorphism for a gene playing an important role in lipoprotein metabolism.

When the genes related to the hormonal regulation of body fat distribution studied in the QFS families sex hormone-binding globulin, 3β-hydroxysteroid dehydrogenase, and glucocorticoid receptor genes were considered along with the knowledge that body fat distribution is influenced by nonpathological variations in the responsiveness to cortisol, it was shown that the less frequent 4.

However, the association with abdominal visceral fat area was seen only in subjects of the lower tertile of the percent body fat level. The consistent association between the glucocorticoid receptor polymorphism detected with Bcl I and abdominal visceral fat area suggested that this gene or a locus in linkage disequilibrium with the Bcl I restriction site may contribute to the accumulation of abdominal visceral adipose tissue With respect to the linkage studies, only a few studies of body fat or fat distribution with random genetic markers or candidate genes have been reported using the sibling-pair linkage method.

One of the few reported studies relative to the visceral fat mass was the evaluation of a sib-pair linkage analysis from the QFS between five microsatellite markers encompassing about 20 cM in the Mob-1 region of the human chromosome 16pp These results suggested to the authors that this region of the human genome contains a locus affecting the amount of visceral fat and lipid metabolism as also shown by the association studies indicated above.

The other population and intrafamily association study used a polymorphic marker LIPE in the hormone-sensitive lipase gene, located on chromosome 19q In conclusion, despite the fact that the genetic architecture of obesity has just begun, the results obtained so far suggest that a great number of genes, loci, or chromosomal regions distributed on different chromosomes could play a role in determining body fat and fat distribution in humans.

This reflects the complex and heterogeneous nature of obesity. The accumulation of adipose tissue in the abdominal region is at least partially influenced by genes, which becomes more evident as the number of involved genes are identified.

The concept that adipocytes are secretory cells has emerged over the past few years. Adipocytes synthesize and release a variety of peptide and nonpeptide compounds; they also express other factors, in addition to their ability to store and mobilize triglycerides, retinoids, and cholesterol.

These properties allow a cross-talk of adipose tissue with other organs as well as within the adipose tissue.

The important finding that adipocytes secrete leptin as the product of the ob gene has established adipose tissue as an endocrine organ that communicates with the central nervous system. As already mentioned, LPL is the key regulator of fat cell triglyceride deposition from circulating triglycerides.

LPL is found, after transcytosis, associated with the glycosaminoglycans present in the luminal surface of the endothelial cells. The regulation of LPL secretion, stimulated by the most important hormonal regulator, insulin, is related to posttranslational changes in the LPL enzyme, at the level of the Golgi cisternae and exocytotic vesicles, insulin possibly having a positive role in this secretory process Genes encoding LPL were not differentially expressed in omental when compared with subcutaneous adipocytes However, in very obese individuals omental adipocytes express lower levels of LPL protein and mRNA than do subcutaneous fat cells The regulation of LPL in obesity has been presented in the Section on correlations of abdominal visceral fat.

With respect to the hormonal regulation of LPL, insulin and glucocorticoids are the physiological stimulators of the LPL activity, and their association plays an important role in the regulation of body fat topography.

In effect, omental adipose tissue is known to be less sensitive to insulin, both in the suppression of lipolysis and in the stimulation of LPL However, when exposed to the combination of insulin plus dexamethasone in culture for 7 days, large increases in adipose LPL were observed because of increases in LPL mRNA Significant differences were observed between men and women.

The increase in LPL in response to dexamethasone suggests that the well known steroid-induced adipose redistribution especially in the abdomen may be caused by increases in LPL, which would lead to a preferential distribution of plasma triglyceride fatty acids to the abdominal depot.

Therefore, these data suggest that LPL is central to the development of abdominal visceral obesity On the other hand, catecholamines, GH, and testosterone in males reduce adipose tissue LPL Acylation-stimulating protein ASP. ASP is considered the most potent stimulant of triglyceride synthesis in human adipocytes yet described.

Its generation is as follows Human adipocytes secrete three proteins of the alternate complement pathway: C3 the third component of the complement , factor B, and factor D adipsin , which interact extracellularly to produce a amino-terminal fragment of C3 known as C3a.

Excess carboxypeptidases in plasma rapidly cleave the terminal arginine from C3a to produce the amino acid peptide known as C3a desarg or ASP, which then acts back upon the adipocyte, causing triglyceride synthesis to increase. As fatty acids are being liberated from triglyceride-rich lipoproteins and chylomicrons as the result of the action of LPL, ASP is also being generated and triglyceride synthesis increased concurrent with the need to do so.

In human adipose tissue, in the postprandial period, ASP secretion and circulating triglycerides clearance are coordinated in accordance with the suggestion that ASP in sequence to LPL would have a paracrine autoregulatory role.

The adipsin-ASP pathway, therefore, links events within the capillary space to the necessary metabolic response in the subendothelial space, thus avoiding the excess buildup of fatty acids in the capillary lumen.

The generation of ASP is triggered by chylomicrons. While insulin decreases gene expression of C3, B, and adipsin, it enhances the secretion of ASP as expected from the concurrent action of LPL and ASP. However, more intensely and independent of insulin, ASP is capable of stimulating triglyceride synthesis in adipocytes and fibroblasts.

Thus, from the reduced sensitivity to insulin in the suppression of lipolysis and stimulation of LPL by the omental adipose tissue, omental obesity may represent an example of impaired activity of the ASP pathway even if dysfunction of the pathway is a secondary feature. As a consequence, omental adipose tissue, as compared with subcutaneous fat tissue, would have a limited capacity to prevent fatty acids from reaching the liver, which may contribute to the abnormalities in metabolism observed in visceral obesity Cholesteryl-ester transfer protein CETP.

Human adipose tissue is rich in CETP mRNA, probably one of the major sources of circulating CETP in humans. CETP promotes the exchange of cholesterol esters of triglycerides between plasma lipoproteins.

In this way, the adipose tissue is a cholesterol storage organ in humans and animals; peripheral cholesterol is taken up by HDL species, which act as cholesterol efflux acceptors, and is returned to the liver for excretion , The few studies of circulating CETP in obesity have shown that activity and protein mass of CETP are both significantly increased in obesity, being negatively correlated with HDL cholesterol and the cholesteryl ester-triglyceride ratio of HDL2 and HDL3, thus exhibiting an atherogenic lipoprotein profile.

Furthermore, there was a positive correlation with fasting plasma insulin and blood glucose, suggesting a possible link to insulin resistance — From an observation of Angel and Shen , it could be suggested that the CETP activity of omental adipose tissue is greatly increased in comparison with subcutaneous fat.

Retinol-binding protein RBP. Adipose tissue is importantly involved in retinoid storage and metabolism. RBP is synthesized and secreted by adipocytes , the rate of RBP gene transcription being induced by retinoic acid The mRNA encoding RBP is expressed at a relatively high level in adipocytes with no difference between subcutaneous and omental fat cells There are no data regarding retinol mobilization from adipose stores in humans; however, in vitro studies with murine adipocytes showed that the cAMP-stimulated retinol efflux from fat cells was not the result of increased RBP secretion but instead due to the hydrolysis of retinyl esters by the cAMP-dependent hormone-sensitive lipase PAI-1 is a serine protease inhibitor and evidence suggests that it is a major regulator of the fibrinolytic system, the natural defense against thrombosis.

It binds and rapidly inhibits both single- and two-chain tissue plasminogen activator tPA and urokinase plasminogen activator uTPA , which modulate endogenous fibrinolysis.

The major sources of PAI-1 synthesis are hepatocytes and endothelial cells, but platelets, smooth muscle cells, and adipocytes are also contributors The increased gene expression and secretion of PAI-1 by adipose tissue contribute to its elevated plasma levels in obesity, presenting a strong correlation with parameters that define the insulin resistance syndrome, in particular with fasting plasma insulin and triglycerides, BMI, and visceral fat accumulation: omental adipose tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, and transforming growth factor-βl increased PAI-1 antigen production In a premenopausal population of healthy women with a wide range of BMI, there was a positive correlation of PAI-1 activity with CT-measured visceral fat area, independent of insulin and triglyceride levels.

Weight loss confirmed this link. PAI-1 diminution was correlated only with visceral adipose tissue area loss and not with total fat, insulin, or triglyceride decrease Results from in vitro studies have shown that insulin — stimulates PAI-1 production by cultured endothelial cells or hepatocytes.

Attempts to extrapolate these in vitro data to in vivo proved difficult. Acute 2-h hyperinsulinemia modulation of plasma insulin in humans did not affect PAI-1 levels, and hypertriglyceridemia from several origins was not always associated with increased PAI-1 levels In the same way, exogenous short-term insulin infusion with triacylglycerol and glucose failed to demonstrate elevations of PAI-1 The augmentation of PAI-1 by insulin probably requires concomitant elevation of lipids and glucose and perhaps other metabolites in blood, as suggested by the strikingly synergistic effects when Hep G2 cells are exposed to both insulin and fatty acids in vitro Accordingly, a hyperglycemic hyperinsulinemic clamp associated with an intralipid infusion for 6 h, to induce hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia, produced an increase in PAI-1 concentrations in blood for as long as 6 h after cessation of the infusion However, the extent to which elevation of any one constituent or any given combination of elevations is sufficient to induce the phenomenon has not yet been elucidated in insulin-resistant patients.

In effect, the reduction of PAI-1 after weight loss related more to the degree of weight reduction than to triglyceride or insulin changes, as above indicated, and the lack of increase of PAI-1 in type 2 diabetics without obesity , strongly suggesting that visceral fat is an important contributor to the elevated plasma PAI-1 level observed in visceral obesity independent of insulin, triglyceride, and glucose level.

Finally, prospective cohort studies of patients with previous myocardial infarction or angina pectoris have underlined the association between an increase in plasma PAI-1 levels and corresponding defective fibrinolysis and the risk of atherosclerosis and thrombosis, particularly in relation to coronary events , thus linking visceral fat accumulation to macrovascular disease Recently, it was shown that in addition to insulin, corticosteroids dexamethasone and hydroxycorticosterone affect PAI-1 synthesis by human subcutaneous adipose tissue explants in a dose-dependent manner; this model showed the regulation of PAI-1 by adipose tissue after validation by showing a high correlation between the production of PAI-1 by omental and subcutaneous fat In the same way, it was demonstrated that PAI-1 production was significantly correlated with that of tumor necrosis factor-α TNFα , emphasizing a possible local contribution of TNFα in the regulation of PAI-1 production by human adipose tissue P aromatase activity in adipose tissue is important for estrogen production, which may have a paracrine role, since, as previously indicated, estrogen receptors are expressed in human adipose tissue In effect, estrone, the second major human circulating estrogen in premenopausal women and the predominant one in postmenopausal women, is mostly derived from the metabolism of ovarian-secreted estradiol catalyzed by 17β-hydroxy steroid dehydrogenase and from aromatization of androstenedione in adipose tissue in the former and almost exclusively by aromatization of that C19 androgen secreted by the adrenals in the latter.

The peripheral aromatization of testosterone to estradiol and estrone contributes minimally to estradiol and estrone production The conversion rate of androstenedione to estrone increases as a function of aging and obesity [due to an increase in adipose tissue P aromatase transcript levels, highest in the buttocks, next highest in the thighs, and lowest in the subcutaneous abdominal tissue , ] and significantly greater in women with lower gynoid obesity than in upper body obesity In obese men, the peripheral conversions of testosterone to estradiol and androstenedione to estrone, as well as the circulating levels of those estrogens, are also increased in proportion to the degree of obesity , However, only plasma levels of estrone had a significant correlation with CT-derived abdominal visceral fat and femoral areas Since the increased metabolism of testosterone to estradiol did not account for the major increase in estradiol production in obese men , it is probable that estradiol is secreted or is produced from the peripheral conversion of estrone, as observed in postmenopausal women.

The most abundant adrenal steroid, dehydroepiandrosterone sulfate DHEA-S can also form the active sex steroids, dihydrotestosterone and estradiol, in several tissues, including mesenteric fat The active androgens and estrogens made locally in peripheral tissues, especially adipose fat, exert their action by interacting with the corresponding receptors in the same or nearby cells where their synthesis took place before being released in the extracellular environment as such or as inactive metabolites.

The aromatase enzyme responsible for transforming androstenedione into estrone is present in nonendocrine tissues, particularly adipocytes and adipose stromal cells, the level of aromatase activity in stromal cells being greater than that in adipocytes Insulin and cortisol independently induce preadipocyte differentiation with both having a synergistic effect The intrinsic gender differences in preadipocytes could contribute to a gender-specific pattern of fat distribution Leptin is the product of the obesity ob gene, which is expressed in adipocytes , The human ob gene spans approximately 20 kb and exists in a single copy on chromosome 7q Several studies in rodents suggest that leptin acts as a signaling factor from adipose tissue to the central nervous system, regulating food intake and energy expenditure.

It is hypothesized that via this leptin feedback loop, homeostasis of body weight and a constant amount of body fat are achieved In humans, a strong positive correlation is observed between serum leptin levels and the amount of body fat and adipocyte leptin mRNA as in rodents , The results are in accordance with the in vitro data indicating that leptin secretion is a reflection of fat hypertrophy.

The adipocyte is the only known source of the ob gene product, leptin, as the preadipocytes do not present this capacity The subcutaneous-omental ratio of leptin mRNA expression was markedly higher in women than in men.

Part of the results, according to the authors, could be explained, particularly in women, by the fact that subcutaneous adipocytes are larger than omental adipocytes and as adipocytes increase in size, the leptin mRNA is up-regulated such that it forms a greater proportion of the total mRNA than in smaller adipocytes.

Indeed, increased leptin mRNA expression in large adipocytes has been reported by Hamilton et al. Furthermore, leptin expression and levels increase as the size of the adipose tissue triglyceride stores increase In a study examining the secretion of leptin in subcutaneous and omental fat tissue from obese and nonobese women, it was shown that the leptin secretion rate and leptin mRNA expression were about 2 to 3 times higher in the subcutaneous than in the omental fat tissue in both obese and nonobese subjects.

There was a positive correlation between BMI and leptin secretion rates in subcutaneous and omental fat tissue. Furthermore, leptin secretion rates in both fat tissues had a high positive correlation with serum leptin levels. Serum leptin circulates, in part, bound to transport proteins in the serum of both rodents and humans, and the size distribution of endogenous serum leptin, as determined by RIA after sucrose gradient centrifugation, is consistent with saturation of binding in hyperleptinemic obesity.

Thus, in humans, free leptin increases with BMI For individuals with the same BMI, the leptin circulating levels can vary by 1 order of magnitude , suggesting that leptin is regulated by factors other than the size of the adipose tissue depot.

In effect, the secretion of leptin by adipocytes is regulated by nutritional and hormonal factors. Acute changes in energy balance appear to regulate leptin expression and circulating levels. On the other hand, both leptin expression and levels decline rapidly in response to starvation, with serum leptin levels starting to decline after 12 h of fasting and reaching a nadir after 36 h, out of proportion to body adiposity changes , Thus, under conditions of steady-state energy balance, leptin is a static index of the amount of triglyceride stored in adipose tissue and in non-steady-state energy balance situations.

Leptin may be acutely regulated independently of the available adipose tissue triglyceride stores and may serve as a sensor of energy balance However, the precise mechanism mediating the distinct responses to changes in body adiposity and energy balance remains to be elucidated.

In rodents, the decreased ob gene expression after fasting and increase after realimentation appear to be related, according to in vitro data, to a transcriptional direct effect of insulin , , In humans, the positive effects of insulin are controversial in vivo. Experiments in vitro have not solved the controversy over the potential effects of insulin on leptin synthesis, as both an increase and no change have been reported Dose-response and time-course characteristics of the effect of insulin on plasma leptin in normal men during a 9-h euglycemic clamp indicated that physiological insulinemia acutely increases leptin by comparison with a control saline infusion.

Plasma leptin also showed a dosage-dependent increase during the insulin infusion The hormonal regulation glucocorticoids and insulin of leptin synthesis was studied by Halleux et al.

They found that glucocorticoids, at physiological concentrations, stimulated leptin secretion by enhancing the pretranslational machinery in human visceral fat. This effect was more pronounced in obese subjects due to a greater responsiveness of the ob gene.

Unlike glucocorticoids, insulin had no direct stimulatory effect on ob gene expression and leptin secretion and even prevented the positive response to dexamethasone by a cAMP-independent mechanism that remained functional despite insulin resistance.

Serum leptin concentrations in humans exhibit a sexual dimorphism, with circulating levels being higher in women than in men. Although women tend to have a higher fat mass than men for the same BMI, this dimorphism appears to occur independently of body adiposity Two factors are related to the sexual dimorphism of serum leptin.

The first is the higher ratio of subcutaneous to omental fat mass 7 and since a significantly higher subcutaneous-omental fat ratio of leptin expression was demonstrated in women, as above indicated , the higher serum leptin levels in women could reflect, at least partially, these gender variations in regional body fat distribution and leptin expression.

The second factor is the prevailing sex steroid milieu. Cross-sex hormone administration in transsexual subjects showed that subjects with high circulating testosterone, whether male or female, had significantly lower serum leptin at a certain degree of body fatness compared with subjects male or female with high estrogen and low testosterone levels.

These results indicated that sex hormone steroids, in particular testosterone, play an important role in the regulation of serum leptin levels, concluding that the prevailing sex steroid milieu, not genetic sex, is the significant determinant of the sex difference in serum lipids It was shown that TNFα positively modulates leptin secretion by adipocytes ; thus, increased TNFα expression in adipose cells seen in obesity could be related to the hyperleptinemia found in this situation.

In effect, a positive independent association was shown between circulating levels of leptin and of circulating soluble human kDa TNFα receptor, which has been validated as a sensitive indicator of activation of the TNFα system in healthy young controls and type 2 diabetics.

This reflects an association between leptin and the TNFα system in humans similar to that seen in rodents, where TNFα and interleukins increase leptin gene expression and circulating leptin levels , All experimental studies indicated that the central nervous system is a major site of leptin action, inducing a reduction in activity of orexigenic and an activation of anorexigenic neurons , Moreover, leptin may affect neuroendocrine mechanisms other than regulation of food intake, which will not be discussed in the present review.

Furthermore, it is being increasingly appreciated that leptin may also act in the periphery. Thus, leptin has been shown to reduce lipid synthesis in cultured adipocytes as well as decrease triglyceride synthesis and increase fatty acid oxidation in normal pancreatic islet cells in short-term culture Normal rats made chronically hyperleptinemic exhibit a prompt and sustained reduction in food intake and disappearance of all visible body fat, associated with hypoglycemia, as well as hypoinsulinemia associated with complete depletion of islet cell triglyceride content, unresponsive to in vitro stimulatory levels of glucose and arginine.

It was concluded that hyperleptinemia causes reversible β-cell dysfunction by depleting tissue lipids, thereby depriving β-cells of a lipid signal required for the insulin response to other fuels This finding, in combination with the previous observation that insulin stimulates leptin secretion and the demonstration of leptin receptors on human islets β-cells, and that leptin suppresses insulin secretion and gene expression, suggests the existence of an adipoinsular axis in rodents and humans in which insulin stimulates leptin production in adipocytes, and leptin inhibits the production of insulin in β-cells There are also actions of leptin on other organ systems, apart from the nervous system and endocrine-metabolic realms.

Angiotensinogen is synthesized primarily by the liver and secreted abundantly by the adipose tissue. Its gene expression in fat tissue is regulated by glucocorticoids and cleaved in the circulation by renin to angiotensin I, which is subsequently converted to angiotensin II by angiotensin-converting enzyme; both enzymes are also expressed in adipose tissue Thus, angiotensin II, produced locally in adipose tissue, can induce preadipocytes to differentiate into adipocytes by stimulating prostacyclin production from adipocytes It was found that in nonobese and obese rats, angiotensinogen protein and correspondent mRNA are about 2-fold higher in visceral adipose tissue than in subcutaneous sites, and its production increases concomitantly with the development of obesity in the obese Zucker rat , Since adipose tissue constitutes the most important source of angiotensinogen after the liver, it cannot be excluded that, in addition to its effect on the development of adipose tissue, an enhanced secretion of angiotensinogen, via angiotensin II, could lead to the increased levels of blood pressure frequently observed in obesity The angiotensinogen mRNA expressed in subcutaneous abdominal adipocytes was greater in obese than in lean subjects, but not significantly so.

Further, no significant differences were found between obese patients with and without hypertension in the small numbers of subjects studied Through an extensive search of the human adipose tissue cDNA library, Matsuzawa and co-workers isolated a novel cDNA encoding a collagen-like secretory protein that was named adiponectin.

Adiponectin was demonstrated to be specifically and abundantly expressed in adipose tissue; it is detected in human plasma and analyzed in both by immunoblotting.

In normal male subjects, plasma adiponectin levels were negatively correlated with BMI and visceral fat area but not with subcutaneous abdominal fat area. Plasma levels in patients with coronary heart disease were lower than those without heart disease, although no difference was observed in BMI or visceral fat area To elucidate the regulation of plasma adiponectin in comparison with leptin levels, the same investigators studied rhesus monkeys with various body weights and also with and without type 2 diabetes.

There was a significant inverse correlation between body weight and plasma adiponectin levels while, as expected, corresponding leptin levels correlated significantly with body weight. With respect to the insulin values, the plasma adiponectin decreased and leptin increased significantly in hyperinsulinemic monkeys.

A longitudinal study in 13 monkeys revealed that the plasma adiponectin decreased as they gained weight, whereas the plasma leptin levels increased. It was concluded that the adiponectin levels would be negatively regulated by adiposity and that the plasma leptin levels were positively regulated by adiposity It was shown that adiponectin inhibited growth factor-induced human aortic smooth muscle cell proliferation Adipocytes are both a source of and a target tissue of the cytokine TNFα, which is absent in the preadipocyte although it is expressed in the adipocyte.

Obese individuals express 2. Similar increases were observed in adipose production of TNFα protein. In obese subjects, high circulating levels were reported, which fell significantly after weight loss In addition, a strong positive correlation is observed between TNFα mRNA expression in fat tissue and the level of hyperinsulinemia, an indirect measure of insulin resistance.

Regarding the molecular mechanism responsible for the decreased insulin action, especially in obesity, it appears to involve TNFα-induced serine phosphorylation of insulin-receptor-substrate- IRS -1 Although there was heterogeneity in mRNA values among obese subjects, there was a consistent reduction in TNFα mRNA expression and protein level of approximately the same magnitude in adipose tissue after weight loss.

In contrast to the marked site-related expression of leptin, as previously indicated, genes encoding TNFα are not differentially expressed in human subcutaneous and omental adipocytes Since the expression of TNFα is negatively correlated with LPL activity in the adipose tissue and is higher in the reduced-obese subjects, the magnitude of these changes did not correlate with each other, suggesting that factors, other than adipocyte TNFα expression, are involved in regulating LPL in the reduced-obese state Together, these studies could suggest a local action of the cytokine, in addition to the existence of some additional local factor, limiting the entrance of fatty acids via LPL and the subsequent hypertrophy of the adipocyte.

In effect, in addition to the decrease in activity of LPL, TNFα has multiple actions in adipose tissue, including a decrease in expression of the glucose transporter GLUT 4 and an increase in hormone-sensitive lipase In a group of male patients with premature coronary heart disease, TNFα levels measured using a sensitive enzyme-linked immunosorbent assay ELISA for human TNFα did not show any relationships either with plasma insulin concentrations or the degree of insulin resistance as measured by the HOMA method a crude measure of insulin resistance.

It appeared from that study that the elevated TNFα circulating levels were associated with atherogenic metabolic disturbances in men with premature coronary heart disease In line with this report is the observation that in subcutaneous adipose tissue taken from lean controls, obese insulin-resistant subjects with normal glucose tolerance, and obese insulin-resistant type 2 diabetics, all males, TNFα mRNA expression was normal in healthy obese men and type 2 diabetic patients; it was not regulated by hyperinsulinemia and was not associated with obesity or insulin resistance, as evaluated by an euglycemic hyperinsulinemic clamp Accordingly, given the well established link between omental adiposity and insulin resistance in humans, if adipocyte TNFα expression is linked to insulin resistance , there should be evidence for a site-related TNFα expression in isolated human adipocytes that has not been observed In addition, Montague et al.

Analysis of the data presented by Kern et al. In addition, preliminary data indicated a trend for a higher release of TNFα in omental than subcutaneous adipose tissue obtained from morbidly obese subjects PPARs are ligand-activated transcription factors of the nuclear hormone receptor superfamily.

Of the three distinct PPAR subtypes, PPAR-γ is highly tissue selective, being most abundant in adipose tissue. PPAR-γ exists in three isoforms, γ-1, -2, and The nature of the endogenous ligand s to PPAR-γ is still unclear, although arachidonic acid metabolites such as deoxy-δ,PGJ 2 , and long-chain fatty acids have been implicated.

Activation of PPAR-γ results in altered expression of selected target genes. PPARs, including PPAR-γ, are only transcriptionally active after heterodimerization with a 9- cis retinoic acid-activated receptor, retinoid X receptor RXR. Such sequences have been identified in the regulatory regions of PPAR-γ-responsive genes[ e.

In a comparison of the mRNA expression levels of PPAR-γ in subcutaneous and omental adipose tissue, Lefebve et al. When the absolute PPAR-γ mRNA values were analyzed, there was no relation with BMI in subcutaneous adipose tissue.

In the omental fat, however, a trend to a positive correlation was observed but it did not reach significance in the population tested, who exhibited a wide range of BMI. The same researchers found a 2-fold reduction in GLUT 4, glycogen synthase, and leptin mRNA expression in omental adipose tissue, suggesting a lower GLUT 4-mediated glucose uptake, and perhaps glucose storage, in omental adipocytes while the total insulin receptor expression was significantly higher in this tissue.

Most of this increase was accounted for by expression of the differentially spliced insulin receptor lacking exon 11, which is thought to transmit the insulin signal less efficiently than the insulin receptor lacking exon This finding is consistent with the reduction in GLUT 4 and glycogen synthase but partially at least for the decrease in leptin gene expression.

This suggests that other regulators of that gene are more likely to participate in the depot-specific difference. With respect to the expression of PPAR-γ splice variants, γ-1 andγ -2, it was demonstrated that PPAR-γ-l is the major isoform in human adipocytes by Western blotting However, Vidal-Puig et al.

On the other hand, Auboeuf et al. In addition, the expression of PPAR-γ isoforms is modulated by caloric intake, i. The two adipogenic hormones, insulin and glucocorticoids, show a synergistic effect to induce PPAR-γ mRNA after in vitro exposition to isolated human adipocytes.

In vivo modulation of human PPAR-γ mRNA by obesity and nutrition could suggest a possible role for PPAR-γ expression in the pathogenesis of altered adipocyte number and function in obesity In effect, PPAR-γ has been shown to induce apoptosis of large adipocytes and the differentiation of small adipocytes in vivo Because smaller adipocytes are usually more sensitive to insulin, such a differentiated response would be expected to produce greater insulin-dependent glucose uptake.

Increasing evidence points to the importance of locally produced cytokines in the regulation of adipocyte metabolism. Among the cytokines, in addition to TNFα, which increases with fat cell enlargement in obesity, adipose tissue also produces another ubiquitous cytokine, interleukin Since the plasma concentration of interleukin-6 is proportional to the fat mass , the adipose tissue could become an important source of that cytokine.

Since interleukin-6 as well as TNFα reduces the expression of LPL, it could have a local role in the regulation of the uptake of fatty acids by the adipose tissue. It is possible that adipose tissue TNFα, whose expression is increased in obesity, induces adipocyte and nonadipocyte interleukin-6 expression.

In effect, TNFα produces a fold increase in interleukin-6 production in differentiated 3T3-L1 adipocytes It was demonstrated that fragments of omental adipose tissue release 2—3 times more interleukin-6 than subcutaneous abdominal adipose tissue, both obtained from severely obese subjects undergoing obesity surgery.

Adipocytes isolated from the omental depot also secrete more interleukin-6 than those from the subcutaneous depot, but other cells within the adipose tissue made a greater contribution to the high release of that cytokine Thus, interleukin-6 may be both an autocrine and a paracrine regulator of adipocyte function in addition to possible effects on other tissues, as stimulation of such acute phase protein synthesis and stimulation of the hypothalamic-pituitary-adrenal axis Because the venous drainage from omental tissue flows directly into the liver, the metabolic impact of interleukin-6 release from omental adipose tissue may be of particular importance, since that cytokine increases hepatic triglyceride secretion , and may, therefore, contribute to the hypertriglyceridemia associated with visceral obesity.

It was demonstrated that cultures of adipose tissue from omental and subcutaneous adipose tissue with glucocorticoids down-regulate the production of interleukin Since interleukin-6 directly stimulates adrenal cortisol release in addition to stimulating hypothalamic CRH and pituitary ACTH release , adipose tissue interleukin-6 may, therefore, act as a feedback regulator of hypothalamic-pituitary axis function.

Cortisol suppression of adipose interleukin-6 production may serve as a feedback inhibitor of this regulatory loop , taking into consideration that increased cortisol turnover is a feature of visceral obesity, as will be discussed later in this review.

Insulin-like growth factor-1 IGF-I. It was shown in preadipocytes from human subcutaneous fat tissue that adipose differentiation induced by the addition of cortisol, insulin, and l-T 3 to a serum-free culture medium was associated with an increase in IGF-I and IGF-binding protein 3 IGFBP3 mRNAs, while the expression of IGF-I receptor IGF-IR mRNA remained relatively stable and the production of IGF-I and IGFBP3 increased greatly.

In preadipocytes, human GH stimulated IGF-I and IGFBP3 mRNA expression as well as an increase in IGF-I and IGFBP3 production, possibly increasing the disposal of free IGF-I. In differentiated adipocytes, human GH stimulated the expression and production of IGFBP3 but not of IGF-I, possibly decreasing the disposal of free IGF-I.

The presence of cortisol led to a decrease of IGFBP3 expression and production in adipocytes. In addition, it was shown that in human adipocytes IGF-1R is expressed in preadipocytes Uncoupling proteins UCPs.

UCPs are mitochondrial membrane transporters that are involved in dissipating the proton electrochemical gradient, thereby releasing stored energy as heat. This implies a major role for UCPs in energy metabolism and thermogenesis, which are key risk factors for the development of obesity and other eating disorders.

At present, three different UCPs have been identified by gene cloning: UCP-1 is expressed in brown adipocytes in rodents inducing heat production by uncoupling respiration from ATP synthesis; UCP-2 is widely expressed in human tissues; and UCP-3 expression is primarily limited to skeletal muscle, an important mediator of thermogenesis in humans Using competitive RT-PCR as a measure, UCP-1 mRNA expression in the visceral adipose tissue of morbidly obese subjects was found to be at significantly lower levels in comparison to controls.

In obese patients, UCP-1 mRNA levels exhibited a strong association with the UCP-1 promoter polymorphism, which was in complete association with four substitutions. Furthermore, there was a borderline significant association of UCP-1 mRNA abundance and the combined effect of Arg64Trp and Gln28Glu substitution of the β 3 - and β 2 -adrenergic receptor, respectively; the mutation of the β 3 -adrenoreceptor was associated with lower lipolytic activity, suggesting that variant forms of adrenergic receptors implicated in obesity may affect UCP-1 expression Kogure et al.

However, genetic analysis of various human cohorts suggested a weak contribution of UCP-1 to control fat content and body weight Oberkofler et al. have also demonstrated reduced UCP-2 mRNA expression levels in visceral adipose tissue in morbid obesity in comparison with control lean subjects.

In both obese and nonobese individuals, UCP-2 mRNA abundance was higher in the intraperitoneal than in the extraperitoneal fat tissue, the UCP-2 mRNA expression not being significantly different between obese and nonobese subjects in the latter In conclusion, the reduction of UCP-1 and -2 mRNA in visceral adipose tissue associated with reduced gene expression of UCP-2, but not UCP-3, in skeletal muscle of human visceral obesity is compatible with a decreased capacity to expend energy in subjects with visceral obesity.

The data indicating that UCP-2 and UCP-3 are involved in energy or proton conductance activities in humans are still quite weak, and the biochemical activities and biological roles of these newly described UCPs remain to be elucidated.

In addition to the secreted ubiquitous angiogenic factors TGFβ and PGE 2 , monobutyrin l-butyryl-glycerol is a specific secretion product of the adipocyte, favoring the vascularization of adipose tissue on development and vasodilation of the microvessels As clearly indicated earlier in this review, individuals with upper-body central obesity, i.

e , fat accumulation in the subcutaneous abdominal and visceral depots, are prone to metabolic and cardiovascular complications, especially when there is excess fat in the visceral area. What is the mechanism behind regional fat distribution, and why is it more dangerous to accumulate fat in the visceral area than in other regions?

The vascular anatomy and the metabolic activity of visceral fat may be the key factors predisposing to complications of obesity Only visceral adipose tissue is drained by the portal venous system and has a direct connection with the liver. Mobilization of FFAs is more rapid from visceral than from subcutaneous fat cells because of the higher lipolytic activity in visceral adipocytes, in both nonobese and obese individuals, particularly in the latter, which probably contributes significantly to the FFA levels in the systemic circulation The higher lipolytic activity in visceral fat in comparison with the subcutaneous adipose tissue can be attributed, as indicated previously, to regional variation in the action of the major lipolysis-regulating hormones, catecholamines and insulin, the lipolytic effect of catecholamines being more pronounced and the antilipolytic effect of insulin being weaker in visceral than in subcutaneous adipose tissue This site variation is related to the increased expression and function of β-adrenoreceptors particularly β 3 associated with a decreased function of α 2 -adrenoreceptor-dependent antilipolysis in the obese and a decreased insulin receptor affinity and signal transduction in visceral adipocytes Table 3.

With respect to the antilipolytic effect of adenosine and prostaglandins produced in adipose tissue, it is equally or slightly more pronounced in subcutaneous than in visceral adipocytes because of decreased agonist receptor number in visceral adipocytes The visceral fat catecholamineinduced lipolysis is greater in obese men than in women; this is partially due to a larger fat cell volume and also to a greater β 3 - and lowerα 2 -adrenoreceptor sensitivity , which results in higher FFA mobilization from visceral fat to the portal system in men than in women.

On the other hand, the antilipolytic effect of insulin is reduced in omental adipocytes regardless of the presence of obesity Table 3. Thus, the enhanced total lipolytic activity probably contributes significantly to the FFA levels in systemic circulation However, in obesity, changes occur in adipocytes that conceivably try to offset the detrimental effects of accelerated lipolysis.

For instance, although the lipolytic response to catecholamines is increased, the sensitivity of abdominal subcutaneous fat to catecholamine-induced lipolysis is decreased in obese women because of a depletion of β 2 -adrenoreceptors This adaptive mechanism of subcutaneous fat cannot be detected in visceral fat of obese individuals, in whom there are normal sensitivities of β 1 and β 2 -adrenoreceptors but markedly increased sensitivity of β 3 -adrenoreceptor-dependent lipolysis and severely decreased sensitivity toα 2 -dependent antilipolysis Table 3.

With respect to the size of the fat depots with relation to LPL activity as well as acylation-stimulating protein as indicated in the adipose tissue LPL activity in Section IV , it was demonstrated, as previously shown 21 , that the uptake of triglycerides is higher in intraabdominal fat and, combined with rapid rate of release of glycerol, is a measurement of lipid mobilization.

This is independent of the degree of BMI, and without correlation with LPL activity, which is expressed equally in human subcutaneous and omental adipocytes In women, but not in men, the omental adipose tissue has smaller adipocytes, and it presents lower LPL activity than subcutaneous fat depots.

The LPL activity is lower in visceral than in subcutaneous fat irrespective of the presence of obesity Table 3.

Obesity adds a generalized increase in lipid turnover sustained by an increased response to lipolytic agents, a reduced effect of antilipolytic hormones, and increased LPL activity, which is most likely due to chronic hyperinsulinemia and playing a role in maintaining excess body fat depots Table 3.

Thus, the visceral fat mass probably contributes significantly to the FFA levels in the systemic circulation However, the elevated exposure of the liver to FFAs from visceral fat in obesity was deduced indirectly rather than measured directly.

Available information does not indicate that visceral adipose tissue contributes much to liver exposure of FFA There is, however, a possibility that, by the addition of portal FFA and FFA in the hepatic artery, the liver is exposed to more than would be predicted from systemic FFA availability data , The elevated FFA flux into the liver would decrease the hepatic insulin extraction by inhibiting insulin binding and degradation , leading to systemic hyperinsulinemia as well as inhibiting the suppression of hepatic glucose production by insulin , In addition, FFAs accelerate gluconeogenesis by providing a continuous source of energy ATP and substrate Center for Human Nutrition and Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St.

Louis, Missouri, USA. Address correspondence to: Samuel Klein, Washington University School of Medicine, South Euclid Avenue, Campus Box , St. Louis, Missouri , USA. Phone: ; Fax: Find articles by Klein, S. in: JCI PubMed Google Scholar.

Published June 1, - More info. Increased plasma fatty acid concentrations may be responsible for many of the metabolic abnormalities associated with abdominal obesity. Excessive visceral fat is associated with insulin resistance and other metabolic risk factors for coronary heart disease. A study reported in this issue of the JCI evaluates the relative contribution of fatty acids released during lipolysis of visceral adipose tissue triglycerides to portal and systemic fatty acid flux in human subjects.

Subsequently, many large epidemiological and smaller physiological studies have confirmed the relationship between abdominal obesity and insulin resistance, diabetes, and other metabolic risk factors for coronary heart disease 2 — 5. In fact, excess abdominal fat is even associated with impaired insulin-mediated glucose uptake in lean adults 6.

Abdominal fat is composed of several distinct anatomic depots: subcutaneous fat, which can be divided into anterior and posterior or superficial and deep layers, and intraabdominal fat, which can be divided into intraperitoneal and retroperitoneal sites.

Intraperitoneal fat, also known as visceral fat, is composed of mesenteric and omental fat masses. Although the absolute amount of each of these depots is much larger in upper-body obese than in lean persons, the relative amount of abdominal fat with respect to total body fat mass is often similar in both groups.

The close relationship between abdominal fat i. Waist circumference is often used as a surrogate marker of abdominal fat because it correlates closely with total abdominal fat mass measured by computed tomography 8 and it is not practical to directly measure abdominal fat mass in a clinical setting.

Based on data from epidemiological studies, the Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, convened by the NIH, proposed that men with a waist circumference greater than cm 40 in.

and women with a waist circumference greater than 88 cm 35 in. are at increased risk for metabolic diseases 9.

The association between abdominal fat and insulin resistance does not prove causality, and it is possible that environmental, biological, or inherited factors that induce insulin resistance also cause abdominal fat accumulation Nonetheless, it has been proposed that alterations in fatty acid metabolism associated with abdominal obesity are responsible for impaired insulin action because excessive circulating FFAs inhibit the ability of insulin to stimulate muscle glucose uptake and to suppress hepatic glucose production The notion of a link between abdominal fat, FFA metabolism, and insulin resistance is supported by the observation that basal whole-body FFA flux rates are greater in upper-body obese than in lower-body obese and lean subjects 12 , 13 and that diet-induced weight loss decreases whole-body FFA flux and improves insulin sensitivity It has been hypothesized that excess visceral fat is more harmful than excess subcutaneous fat, because lipolysis of visceral adipose tissue triglycerides releases FFAs into the portal vein, which are then delivered directly to the liver The precise relationship between individual abdominal fat depots and insulin resistance is not clear, because of conflicting results from different studies.

Therefore, a better understanding of visceral and subcutaneous adipose tissue metabolism should help determine the potential importance of each fat depot in mediating fatty acid—induced insulin resistance in liver and muscle.

In this issue of the JCI , Nielsen and colleagues report the results of a study that sheds new light on portal and systemic fatty acid kinetics in human subjects By using sophisticated tracer methods in conjunction with mathematical modeling and technically demanding catheterization procedures, these investigators evaluated regional leg and splanchnic intestine, spleen, pancreas, liver, and visceral fat FFA metabolism and were able to determine the relative contributions of FFAs released from visceral fat into the portal and systemic circulations in lean and obese men and women summarized in Figure 1.

Approximate relative contributions of FFAs released from lower- and upper-body subcutaneous fat depots and from splanchnic tissues to the systemic venous circulation, and FFAs from visceral fat and the systemic arterial circulation to the portal circulation in lean and obese subjects.

Values are based on data from ref. The results of this study demonstrate that the release of FFAs into the portal vein from lipolysis in visceral fat depots increases with increasing amounts of fat However, the relative contribution at any individual visceral fat mass was quite variable.

Therefore, although there is a direct relationship between visceral fat mass and its contribution to hepatic FFA metabolism, it is impossible to determine which individuals have a high rate of visceral FFA flux based on analysis of body composition and fat distribution alone.

More importantly, the relative amount of portal vein FFAs derived from visceral fat was much less than the relative amount derived from lipolysis of subcutaneous fat.

Researchers have long-known SSubcutaneous visceral Subcutaneous fat and metabolism — the kind Herbal appetite control wraps around the internal organs metabolim is more dangerous Subcutaneeous Subcutaneous fat and metabolism fat that SSubcutaneous just under the skin around the belly, thighs and rear. But how visceral fat contributes to insulin resistance and inflammation has remained unknown. The findings are published in the journal Nature Communications. Obesity and stress on the endoplamic reticulum cause inflammation through upregulation of GATA 3 and TRIP-BR2 in visceral fat. Credit: Chong Wee Liew.

The results of Subcutanous recent studies indicate that there are regional differences Subuctaneous the metabolism of Subcutaneoys fatty depots in obesity. Fat cells are larger in Subcutaneuos femoral metzbolism in Improved lipid oxidation efficiency abdominal Subcutameous.

Lipids are mobilized at a slower rate but synthesized at a Subdutaneous rate adn the former than the latter metabolixm. Fasting is accompanied by an increased rate of fat mobilization and a decreased rate metabolissm fat synthesis in all fat depots.

These changes Subcutanrous, however, more pronounced in abdominal than in Subcutneous fat. There are also fst differences in the hormonal regulation of fat metabollism in obesity.

The action of insulin is most pronounced in the femoral Subcufaneous whereas that Sibcutaneous catecholamines is most marked in the abdominal area. The regional differences in hormone action Subcutanfous further enhanced during fag fasting.

Subcutaneous fat and metabolism differences may partly explain why adiposity is more Plant-based supplement products in some fatty regions Carbohydrate and skin health in others and also why some Subcutaneois areas are resistant to Subcutaheous.

This is mmetabolism preview of subscription Subcutanepus, log in via an metaboljsm to check access. Rent fqt article metbolism DeepDyve. Institutional subscriptions. Amatudra JH, Livingston JN, Cat PH: Rat receptor: Role in the resistance of ajd obesity to insulin.

Science Google Boost mental clarity. Arner P, Bolinder J, Curcumin for Arthritis Plant-based supplement products, Östman J: The antilipolytic effect of insulin in human adipose tissue in obesity, Subcutanfous mellitus, hyperinsulinemia, Subcutaneous fat and metabolism starvation.

Subctaneous 30 Arner P, Ans P, Lithell H: Suubcutaneous differences in the basal metabolism of subcutaneous snd in obese netabolism.

J Shbcutaneous Endocrinol Metab 53 Arner P, Engfeldt P, Nowak Subcutaneoue In vivo observations on the lipolytic effect of qnd during xnd fasting. Fqt P, Engfeldt P, Wennlund A, Östman Znd Post receptor Subcutaneoud of lipolysis in starvation, diabetes mellitus, Sports nutrition for power and agility hyperthyroidism.

Horm Metab Res Subcutaneiusmetabolisk Arner P, Östman J: Changes in the metabklism control and the gat of lipolysis metabbolism isolated human far Plant-based supplement products during Grape Face Mask Recipes and after re-feeding.

Acta Subcutaneous fat and metabolism Metabooismaft Arner P, Subctaneous J: Relationship between metaboliem tissue metabklism cyclic AMP and the fat mefabolism size of metabolsim adipose tissue. J Ans Res 19 Nutrient absorption in the body P, Suvcutaneous J: Vat adipose tissue.

Dynamics wnd regulation. Adv Metab Anx 5Subcutsneous Bolinder J, Engfeldt P, Östman Subcutabeous, Arner P: Site differences in insulin receptor binding and meabolism action in fzt fat of obese females.

Appetite control techniques book Clin Endocrinol Metab Subcutaneous fat and metabolism Ciaraldi TP, Kolterman OG, Fta JM: Mechanisms of the post-receptor defect metaboilsm insulin action in Pancreatic duct obstruction obesity: Metabollsm in glucose transport system activity J Clin Invest 68 Engfeldt Subcutsneous, Arner P, Östman J: Changes in phosphodiesterase Metsbolism of human subcutaneous Subcutanfous tissue during starvation.

Metabolism 31 Subcutaneoous, Subcuhaneous CH, Galton PJ: Metabolixm effect of catecholamines and fasting metabbolism cyclic AMP and release of glycerol from human adipose tissue.

Horm Metab Res 6 Jacobsson B, Holm G, Björntorp P, Smith U: Influence of cell size on the effects of insulin and noradrenalin on human adipose tissue.

Diabetologia 12 Kather H, Zöllig K, Simon B, Schlierf G: Human fat cell adenylate cyclase, regional differences in adrenaline responsiveness. Europ J Clin Invest 7 Kjellberg J, Östman J: Lipolysis and glucose tolerance in obese subjects during prolonged starvation.

Lafontan M, Dang-Tran L, Berlan M: Alpha-adrenergic antilipolytic effect of adrenaline in human fat cells of the thigh: Comparison with adrenaline responsiveness of different fat deposits.

Europ J Clin Invest 9 Lithell H, Boberg J: The lipoprotein-lipase activity of adipose tissue from different sites in obese women and relationship to cell-size. Int J Obesity 2 Olefsky JM: Decreased insulin binding to adipocytes and circulating monocytes from obese subjects. J Clin Invest 57 Östman J, Arner P, Engfeldt P, Kager L: Regional differences in the control of lipolysis in human adipose tissue.

Metabolism 28 Östman J, Arner P, Kimura H, Wahrenberg H, Engfeldt P: Effect of therapeutic fasting on alpha- and beta-adrenergic receptors in subcutaneous adipocytes.

Europ J Clin Invest Submitted. Pedersen O, Hjöllund E, Schwartz Sörensen N: Insulin receptor binding and insulin action in human fat cells: Effects of obesity and fasting.

Vague J, Boyer J, Jubelin J, Nickolino C, Pinto C: Adipo-muscular ratio in human subjects. In Physiopathology of Adipose Tissue, J Vague, R Denton, eds, Amsterdam: Excerpta Medica,p Download references.

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Abstract The results of several recent studies indicate that there are regional differences in the metabolism of subcutaneous fatty depots in obesity. Access this article Log in via an institution. References Amatudra JH, Livingston JN, Lockwood PH: Insulin receptor: Role in the resistance of human obesity to insulin.

ScienceGoogle Scholar Arner P, Bolinder J, Engfeldt P, Östman J: The antilipolytic effect of insulin in human adipose tissue in obesity, diabetes mellitus, hyperinsulinemia, and starvation.

Metabolism 30Google Scholar Arner P, Engfeldt P, Lithell H: Site differences in the basal metabolism of subcutaneous fat in obese women. J Clin Endocrinol Metab 53Google Scholar Arner P, Engfeldt P, Nowak J: In vivo observations on the lipolytic effect of noradrenaline during therapeutic fasting.

J Clin Endocrinol Metab 53Google Scholar Arner P, Engfeldt P, Wennlund A, Östman J: Post receptor activation of lipolysis in starvation, diabetes mellitus, and hyperthyroidism. Horm Metab Res 13Google Scholar Arner P, Östman J: Changes in the adrenergic control and the rate of lipolysis of isolated human adipose tissue during fasting and after re-feeding.

Acta Med ScandGoogle Scholar Arner P, Östman J: Relationship between the tissue level cyclic AMP and the fat cell size of human adipose tissue. J Lipid Res 19 Google Scholar Björntorp P, Östman J: Human adipose tissue. Adv Metab Dis 5Google Scholar Bolinder J, Engfeldt P, Östman J, Arner P: Site differences in insulin receptor binding and insulin action in subcutaneous fat of obese females.

J Clin Endocrinol Metab 57Google Scholar Ciaraldi TP, Kolterman OG, Olefsky JM: Mechanisms of the post-receptor defect in insulin action in human obesity: Decrease in glucose transport system activity J Clin Invest 68Google Scholar Engfeldt P, Arner P, Östman J: Changes in phosphodiesterase activity of human subcutaneous adipose tissue during starvation.

Metabolism 31Google Scholar Gilbert CH, Galton PJ: The effect of catecholamines and fasting on cyclic AMP and release of glycerol from human adipose tissue.

Horm Metab Res 6Google Scholar Jacobsson B, Holm G, Björntorp P, Smith U: Influence of cell size on the effects of insulin and noradrenalin on human adipose tissue. Diabetologia 12Google Scholar Kather H, Zöllig K, Simon B, Schlierf G: Human fat cell adenylate cyclase, regional differences in adrenaline responsiveness.

Europ J Clin Invest 7Google Scholar Kjellberg J, Östman J: Lipolysis and glucose tolerance in obese subjects during prolonged starvation. Acta Med ScandGoogle Scholar Lafontan M, Dang-Tran L, Berlan M: Alpha-adrenergic antilipolytic effect of adrenaline in human fat cells of the thigh: Comparison with adrenaline responsiveness of different fat deposits.

Europ J Clin Invest 9Google Scholar Lithell H, Boberg J: The lipoprotein-lipase activity of adipose tissue from different sites in obese women and relationship to cell-size. Int J Obesity 2Google Scholar Shbcutaneous JM: Decreased insulin binding to adipocytes and circulating monocytes from obese subjects.

J Clin Invest 57Google Scholar Östman J, Arner P, Engfeldt P, Kager L: Regional differences in the control of lipolysis in human adipose tissue.

Metabolism 28Google Scholar Östman J, Arner P, Kimura H, Wahrenberg H, Engfeldt P: Effect of therapeutic fasting on alpha- and beta-adrenergic receptors in subcutaneous adipocytes. Europ J Clin Invest Submitted Pedersen O, Hjöllund E, Schwartz Sörensen N: Insulin receptor binding and insulin action in human fat cells: Effects of obesity and fasting.

Metabolism 31Google Scholar Vague J, Boyer J, Jubelin J, Nickolino C, Pinto C: Adipo-muscular ratio in human subjects. In Physiopathology of Adipose Tissue, J Vague, R Denton, eds, Amsterdam: Excerpta Medica,p Google Scholar Download references. Author information Authors and Affiliations Department of Medicine at the Huddinge Hospital, Karolinska Institute, S 86, Huddinge, Sweden Peter Arner M.

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: Subcutaneous fat and metabolism

Subcutaneous Fat: Purpose and Targeted Weight Loss	Approximate relative contributions of FFAs released from lower- and upper-body subcutaneous fat depots and from splanchnic tissues to the systemic venous circulation, and FFAs from visceral fat and the systemic arterial circulation to the portal circulation in lean and obese subjects. The close relationship between abdominal fat i. Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects. This fat topography was retained in young and middle-aged females up to about 60 yr of age, at which point there was a change to an android type of fat distribution. Again, it was concluded that the WHR is a suboptimal predictor of visceral adipose tissue volume. Back To Top. The results of this study Fig.
Exercise remodels subcutaneous fat tissue and improves metabolism	According to Pouliot et al. The threshold value is similar in men and women in that for a given waist circumference, men and women had comparable levels of abdominal visceral adipose tissue. Thus, waist circumference, a convenient and simple measurement unrelated to height 46 and correlated with BMI and WHR 47 , determines the extension of abdominal obesity, which appears closely linked to abdominal visceral adipose tissue deposition. Furthermore, while changes in waist girth reflect changes in risk factors for cardiovascular disease 48 and other forms of chronic disease, the risks vary in different populations; therefore, globally applicable cut-off points cannot be developed. For example, abdominal fatness has been shown to be less strongly associated with risk factors for cardiovascular disease and type 2 diabetes in black women than in white women Risk factors such as total and HDL cholesterol were correlated with subcutaneous and abdominal fat areas by CT as well as their sum in healthy nonobese Asian Indians. On the other hand, while there was an association of visceral adiposity with insulin secretion during an oral glucose test in men, such was not found in women In addition, it has been reported that visceral obesity is strongly related to coronary heart disease risk factors in nonobese Japanese-American men Also, people of South Asian Indian, Pakistani, and Bangladeshi descent living in urban societies have a higher incidence of obesity complications than other ethnic groups These complications are seen to be associated with abdominal fat distribution, which is markedly higher for a given level of BMI than in Europeans. Finally, although women have an almost equivalent absolute risk of coronary heart disease CHD to men at the same WHR 53 , 54 , they show increases in relative risk of CHD at lower waist circumferences than men. Thus, there is a need to develop sex-specific waist circumference cut-off points appropriate for different populations. The studies by Ferland et al. Therefore, the waist circumference, and the abdominal sagittal diameter as will be discussed below , are the anthropometric indexes preferred over the WHR to estimate the amount of abdominal visceral fat and related cardiovascular risk profile. Using the equations for prediction, multiscan CT was used to determined visceral adipose tissue volume from the waist circumference in a sample of 17 males and 10 females with different degrees of obesity Again, it was concluded that the WHR is a suboptimal predictor of visceral adipose tissue volume. Abdominal sagittal diameter. The sagittal diameter is measured with a ruler as the vertical distance from the horizontal spirit level to the examination table after a normal expiration Kvist et al. The correlation of the sagittal diameter with visceral fat volume was 0. The correlations between the waist circumference and visceral fat were, respectively, 0. These correlations are considerably higher than those observed between anthropometric variables and the visceral fat area measured at the level of the umbilicus in obese men and women Ferland et al. Desprès et al. Busetto et al. It is very likely, therefore, that the range of fatness in subjects studied greatly influences the magnitude of the correlations and perhaps also the comparison between the sagittal diameter and the waist circumference with regard to their utility in predicting intraabdominal fat. In addition, the distinction between studies that used only visceral fat area and those that calculated visceral fat volume from multiple scans may be important to make Ross et al. A study from the Canadian group 38 conducted in a large group of males and females evaluated systematically the three anthropometric indexes and their association with abdominal visceral adipose and subcutaneous areas measured by CT between the fourth and fifth lumbar vertebrae and metabolic profile. As seen in Table 1 , there was a strong association between waist girth and body fat mass, the slope of the regression line being steeper in women data not shown. With relation to the abdominal visceral fat area, for a given waist circumference, men and women had similar levels and the slopes of the regression lines were not different between genders. Essentially similar results were observed with the abdominal sagittal diameter. However, in contrast with waist circumference, the slopes of regression of abdominal sagittal diameter to abdominal visceral fat area were significantly different between genders and were steeper in men data not shown. Finally, it can be seen that the WHR was less strongly correlated with total body fat mass and abdominal visceral and subcutaneous areas than the other indexes. This study demonstrated that most of the variance in waist girth and abdominal sagittal diameter can be explained by variations in body fat mass and in abdominal visceral and subcutaneous adipose tissue areas 0. With relation to the metabolic variables related to cardiovascular risk plasma triglycerides and high-density lipoprotein cholesterol levels, fasting and postglucose glucose and insulin levels , in women, the waist circumference and the abdominal sagittal diameter were more closely related to the metabolic variables than the WHR, whereas such differences were not apparent in men. They concluded that waist circumference values above approximately cm, abdominal sagittal diameter values greater than 25 cm, and WHR values greater than 0. Correlations r values between the anthropometric indexes and body fat mass, abdominal visceral, and abdominal subcutaneous fat areas in 81 men and 70 women. Correlations between sagittal diameter and waist circumference are usually quite high [ e. Although the sagittal supine diameter can be studied with relatively good precision 61 , it is clear that this measurement requires appropriate equipment and skilled personnel. Since most people are measuring the WHR as an indicator of visceral fat, the focus should be switched to the waist girth alone without affecting the ranking of individuals with respect to visceral fat when based on the waist circumference compared with the sagittal diameter Computed tomography CT. CT can be considered the gold standard not only for adipose tissue evaluation but also for multicompartment body measurement 61 , The reported error for the determination of total adipose tissue volume after performing 28 scans is 0. The subcompartments of adipose tissue volume, visceral and subcutaneous adipose tissue, can be accurately measured with errors of 1. In eight nonobese Swedish males evaluated by the multiscan CT technique, the volume of visceral abdominal adipose tissue in the intraperitoneal and retroperitoneal compartments was found to be 1. Using a multislice magnetic resonance protocol, Abate et al. In effect, in 13 lean males, Abate et al. If only one scan is used to measure the visceral adipose tissue area, a strictly defined longitudinal level is very important since the average visceral adipose tissue area shifts if there is a change in position, even of a few centimeters. This, according to Sjöström et al. Instead, the longitudinal level must be defined in a strict relation to the skeleton, usually between the L4 and L5 vertebrae. The subjects are examined in a supine position with their arms stretched above their heads. The choice to perform the scan at the level of the umbilicus was initially proposed by Borkan et al. Subsequently, Tokunaga et al. In addition to the recommendations of the Japanese investigators, studies from Korea 20 and from our clinic use the scan at the umbilicus. Visceral fat is defined as intraabdominal fat bound by parietal peritoneum or transversalis fascia, excluding the vertebral column and the paraspinal muscles; subcutaneous fat is fat superficial to the abdominal and back muscles. Subcutaneous fat area is calculated by subtracting the intraabdominal fat area from the total fat area. In addition, visceral fat increases with age Figure 1 shows cross-sectional abdominal areas obtained by CT at the level of the umbilicus in two women matched for the same BMI, who differed markedly in the accumulation of fat in the abdominal cavity but less so in the subcutaneous abdominal fat. Computed tomography showing cross-sectional abdominal areas at umbilicus level in two patients demonstrating variation in fat distribution. A, Visceral type yr-old female, B, Subcutaneous type yr-old female, In obese subjects the level of the umbilicus can change from one patient to another, thus changing the visceral adipose tissue area; therefore, it is advisable that the scan area be defined in strict relation to the skeleton. Chowdhury et al. However, the values for abdominal cut-off points were related to increased cardiovascular risk Table 2. Using the scan at the umbilicus as described by several investigators gave results similar to, although somewhat lower than, those reported using the L4-L5 level. Abdominal visceral adipose tissue area cut-off points related to increased cardiovascular risk. Regarding the relationship between the modifications in subcutaneous and visceral adipose tissue, with changes in body weight, it was shown that after severe weight loss, subcutaneous fat at the abdominal level is lost in greater proportion than visceral fat, but the mechanism of these differential changes in both compartments of abdominal fat is unknown, suggesting that visceral fat does not reflect nutritional status to the extent that sc fat does In the same way, published data suggest that, at least in relative terms, visceral fat increases less than subcutaneous fat with increased body weight However, because the amount of subcutaneous abdominal fat is calculated indirectly, it is likely that significant measurement error could be introduced Regarding the reproducibility of CT measurement of visceral adipose tissue area, Thaete et al. The duplication occurred after the initial scan; the subjects were repositioned before repeat scanning. As indicated in the Introduction , individuals with a high accumulation of visceral abdominal fat, as shown by CT scans, had an increased risk for development of type 2 diabetes, dyslipidemia, and coronary heart disease. Table 2 shows the thresholds above which metabolic complications would be more likely to be observed in visceral adipose tissue areas. Desprès and Lamarche 73 , Hunter et al. They found that a value above cm 2 was associated with an increased risk of coronary heart disease in pre and postmenopausal women 75 ; the same group 74 found that males with abdominal visceral fat cross-section areas measuring more than cm 2 were clearly at an increased risk for coronary disease. On the other hand, Desprès and Lamarche 73 found that in both men and women a value of cm 2 was associated with significant alterations in cardiovascular disease risk profile and that a further deterioration of the metabolic profile was observed when values greater than cm 2 of visceral adipose tissue were reached. From the same center, Lemieux et al. It was concluded that waist circumference was a more convenient anthropometric correlate to visceral adipose tissue because its threshold values did not appear to be influenced by sex or by the degree of obesity. Anderson et al. The most extensive studies using a single CT scan at umbilical level was done by Matsuzawa and colleagues 17 , However, they did not present the raw data on visceral and subcutaneous areas but only their ratios, thus precluding their inclusion in Table 2. In another study, performed in Japan by Saito et al. Lottenberg et al. Magnetic resonance imaging MRI. MRI provided results similar to CT without exposure to ionizing radiation, the main problem with CT multislice measurements. It demonstrated good reproducibility for total and visceral adipose tissue volumes 63 , which were slightly lower than previously reported using CT 55 , although the percent contribution of visceral to total adipose tissue volume was similar 18 vs. Subcutaneous adipose tissue and visceral fat areas at the L4-L5 level determined in 27 healthy men by MRI were These areas were highly predictive of the corresponding volume measurements computed from the scan MRI, confirming the CT studies of Kvist et al. Two studies have compared estimates of subcutaneous and visceral adipose tissue by CT and MRI. Comparison between MRI and CT in seven subjects showed a high degree of agreement in measurement of total subcutaneous adipose tissue area but not visceral adipose tissue area As already mentioned, MRI has been validated in three cadavers, confirming its accuracy Ultrasound US. US subcutaneous and intraabdominal thicknesses, the latter corresponding to the distance between abdominal muscle and aorta, were measured 5 cm from the umbilicus on the xipho-umbilical line with a 7. The intraindividual reproducibility of US measurements was very high both for intraabdominal and subcutaneous thickness as well as for interoperators 83 , Several studies demonstrated a highly significant correlation between the intraabdominal adipose tissue determined by CT and by US. A decade ago, Armellini et al. In a more recent study, Tornaghi et al. In a study of men C. Leite, D. Matsuda, B. Wajchenberg, G. Cerri, and A. Halpern, unpublished data , in which In obese women, after a 6-kg weight loss, a significant decrease was found in intraabdominal fat but not in subcutaneous adipose tissue, as determined by both CT and US There was also a significant correlation between changes in intraabdominal adipose tissue using both techniques, indicating that US can be used in the evaluation of body fat distribution modifications during weight loss. This is another confirmation of the reliability of the US intraabdominal determinations. The amount of visceral fat increases with age in both genders, and this increase is present in normal weight BMI, In a study of subjects 62 males and 68 females with a wide range of age and weight , Enzi et al. This fat topography was retained in young and middle-aged females up to about 60 yr of age, at which point there was a change to an android type of fat distribution. This age-related redistribution of fat is due to an absolute as well as relative increment in visceral fat depots, particularly in obese women, which could be related to an increase in androgenic activity in postmenopausal subjects. On the other hand, they showed that males at any age tend to accumulate fat at the visceral depot, increasing with age and BMI increase. In the male, a close linear correlation between age and visceral fat volume was shown, suggesting that visceral fat increased continuously with age Although this correlation was also present in women, the slope was very gentle in the premenopausal condition. It became steeper in postmenopausal subjects, almost the same as in males Further, Enzi et al. From the published data 68 , 90 , it can be concluded that both subcutaneous and visceral abdominal fat increase with increasing weight in both sexes but while abdominal subcutaneous adipose tissue decreases after the age of 50 yr in obese men, it increases in women up to the age of 60—70 yr, at which point it starts to decline Fowler et al. Finally, as previously indicated, visceral fat is more sensitive to weight reduction than subcutaneous adipose tissue because omental and mesenteric adipocytes, the major components of visceral abdominal fat, have been shown to be more metabolically active and sensitive to lipolysis Lemieux et al. In addition, the adjustment for differences in visceral fat between men and women eliminated most of the sex differences in cardiovascular risk factors. There is evidence supporting the notion that abdominal visceral fat accumulation is an important correlate of the features of the insulin-resistant syndrome 23 , 24 , 29 but this should not be interpreted as supporting the notion of a cause and effect relationship between these variables This subject will be discussed later on. The correlations of abdominal visceral fat mass evaluated by CT or MRI scans with total body fat range from 0. They tend to be lower in the lean and normal weight subjects than in the obese As indicated by Bouchard et al. When they examined the relationship of total body fat mass to visceral adipose tissue accumulation in men and in premenopausal women, Lemieux et al. Furthermore, the relationship of visceral adipose tissue to metabolic complications was found to be independent of concomitant variation in total body fat, and it was concluded that the assessment of cardiovascular risk in obese patients solely from the measurement of body weight or of total body fatness may be completely misleading 19 , 22 , 36 , Indeed, it appears that only the subgroup of obese individuals characterized by a high accumulation of visceral adipose fat show the complications predictive of type 2 diabetes and cardiovascular disease On the other hand, after adjustment for total body fat, Abate et al. Intraabdominal visceral fat is associated with an increase in energy intake but this is not an absolute requirement. Positive energy balance is a strong determinant of truncal-abdominal fat as shown by Bouchard and colleagues 96 in overfeeding experiments in identical twins. The correlations between gains in body weight or total fat mass with those in subcutaneous fat on the trunk reached about 0. In contrast, these correlations attained only 0. Thus, positive energy balance does not appear to be a strong determinant of abdominal visceral fat as is the case with other body fat phenotypes 7. In effect, as discussed in the CT section of imaging techniques for evaluation of intraabdominal visceral fat, some investigators 70 , 71 have shown that either when the subjects lose or increase their weight, particularly females, visceral fat is lost or gained, respectively, less than subcutaneous fat at the abdominal level. However, at variance from these data, Zamboni et al. Similarly, as already mentioned, Smith and Zachwieja 32 noted that all forms of weight loss affect visceral fat more than subcutaneous fat percentage wise , and there was a gender difference, with men appearing to lose more visceral fat than women for any given weight loss. LPL activity, being related to the liberation of the lipolytic products [from chylomicra and very-low-density lipoproteins VLDL ] to the adipocytes for deposit as triglycerides, is a key regulator of fat accumulation in various adipose areas, since human adipose tissue derives most of its lipid for storage from circulating triglycerides. However, adipocytes can synthesize lipid de novo if the need arises, as in patients with LPL deficiency According to Sniderman et al. The increase of visceral fat masses with increasing total body fat was explained by an increase of fat cell size only up to a certain adipocyte weight. However, with further enlargement of intraabdominal fat masses with severe obesity, the number of adipocytes seems to be elevated , In women, but not in men, omental adipose tissue has smaller adipocytes and lower LPL activity than subcutaneous fat depots since variations in LPL activity parallel differences in fat cell size 7. When adipocytes enlarge in relation to a gain in body weight, the activity of LPL increases in parallel, possibly as a consequence of obesity-related hyperinsulinism. The higher basal activity of adipose tissue LPL in obesity is accompanied by a lower increment after acute hyperinsulinemia Lipid accumulation is favored in the femoral region of premenopausal women in comparison with men In the latter, LPL activity as well as the LPL mRNA levels were greater in the abdominal than in gluteal fat cells, while the opposite was observed in women, suggesting that regional variation of gene expression and posttranslational modification of LPL could potentially account for the differences between genders in fat distribution With progressive obesity, adipose tissue LPL is increased in the depots of fat in parallel with serum insulin. However, when obese subjects lost weight and became less hyperinsulinemic, adipose LPL increased further and the patients who were most obese showed the largest increase in LPL, suggesting that very obese patients are most likely to have abnormal LPL regulation, independent of the influence of insulin. In response to feeding, the increase in LPL is, as indicated, due to posttranslational changes in the LPL enzyme. However, the increased LPL after weight loss involved an increase in LPL mRNA levels, followed by parallel increases in LPL protein and activity Because the response to weight loss occurred via a different cellular mechanism, it is probably controlled by factors different from the day-to-day regulatory forces. In addition, because the very obese patients demonstrated a larger increase in LPL with weight loss than the less obese patients, these data suggest a genetic regulation of LPL that is most operative in the very obese The role of sex steroids, glucocorticoids, and catecholamines in the regulation of adipose tissue LPL activity in various fat depots will be discussed in the section on hormonal regulation of abdominal visceral fat. Lipid mobilization and the release of FFA and glycerol are modulated by the sympathetic nervous system. Catecholamines are the most potent regulators of lipolysis in human adipocytes through stimulatory β l - and β 2 -adrenoreceptors or inhibitoryα 2-adrenoreceptors A gene that codes for a third stimulatory β -adrenoreceptor, β 3 -adrenoreceptor, is functionally active principally in omental adipocytes but also present in mammary fat and subcutaneous fat in vivo In both genders and independently of the degree of obesity, femoral and gluteal fat cells exhibit a lower lipolytic response to catecholamines than subcutaneous abdominal adipocytes, the latter showing both increased β l - and β 2 -adrenoreceptor density and sensitivity and reduced α2-adrenoreceptor affinity and number Refs. The increased sensitivity to catecholamine-induced lipolysis in omental fat in nonobese individuals is paralleled by an increase in the amount of β l - and β 2 -receptors, with normal receptor affinity and normal lipolytic action of agonists acting at postadrenoreceptor steps in the lipolytic cascade , ; this is associated with enhanced β 3 -adrenoreceptor sensitivity, which usually reflect changes in receptor number in comparison with subcutaneous adipocytes , Comparison of lipolysis, antilipolysis, and lipogenesis in omental and subcutaneous fat in nonobese and obese individuals. Adipocytes from obese subjects generally show increased lipolytic responses to catecholamines, irrespective of the region from which they are obtained, and enhanced lipolysis in abdominal compared with gluteo-femoral fat 21 , The antilipolytic effect is also reduced in vitro in obesity, both in omental and subcutaneous adipocytes The typical features of visceral fat, e. An increased β 3 -adrenoreceptor sensitivity to catecholamine stimulation may lead to an increased delivery of FFA into the portal venous system, with several possible effects on liver metabolism. These include glucose production, VLDL secretion, and interference with hepatic clearance of insulin , resulting in dyslipoproteinemia, glucose intolerance, and hyperisulinemia. Lönnqvist et al. They observed that males had a higher fat cell volume with no sex differences in the lipolytic sensitivity to β l - and β 2 -adrenoreceptor-specific agonists or in the antilipolytic effect of insulin. However, the lipolytic β 3 -adrenoreceptor sensitivity was 12 times higher in men, and the antilipolytic α2-adrenoreceptor sensitivity was 17 times lower in men. It was concluded that in obesity, the catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women. This phenomenon is partly due to a larger fat cell volume, a decrease in the function ofα 2-adrenoceptors, and an increase in the function of β 3 -adrenoreceptors. These factors may contribute to gender-specific differences observed in the metabolic disturbances accompanied by obesity, i. Glucocorticoid receptors. Glucocorticoid receptors, one of the most important receptors for human adipose tissue function, are involved in metabolic regulation and distribution of body fat under normal as well as pathophysiological conditions. Glucocorticoid receptors in adipose tissue show a regional variation in density with elevated concentrations in visceral adipose tissue In spite of the lower receptor density, the elevated cortisol secretion results in clearly increased net effects of cortisol. Androgen and estrogen receptors. Adipocytes have specific receptors for androgens, with a higher density in visceral fat cells than in adipocytes isolated from subcutaneous fat. Unlike most hormones, testosterone induces an increase in the number of androgen receptors after exposure to fat cells , thereby affecting lipid mobilization. This is more apparent in visceral fat omental, mesenteric, and retroperitoneal because of higher density of adipocytes and androgen receptors, in addition to other factors However, at variance with the effects of testosterone, dihydrotestosterone treatment does not influence lipid mobilization In females, there is an association between visceral fat accumulation and hyperandrogenicity, despite the documented effects of testosterone on lipid mobilization and the expected decrease in visceral fat depots. The observation that visceral fat accumulation occurs only in female-to-male transsexuals after oophorectomy suggests that the remaining estrogen production before oophorectomy was protective The androgen receptor in female adipose tissue seems to have the same characteristics as that found in male adipose tissue. However, estrogen treatment down-regulates the density of this receptor, which might be a mechanism whereby estrogen protects adipose tissue from androgen effects. Estrogen by itself seems to protect postmenopausal women receiving replacement therapy from visceral fat accumulation Estrogen receptors are expressed in human adipose tissue and show a regional variation of density, but whether the quantity of these receptors is of physiological importance has not been clearly established With regard to progesterone, adipose cells seem to lack binding sites and mRNA for progesterone receptors, indicating that progesterone acts through glucocorticoid receptors GH receptors. While it is well established that GH has specific and receptor-mediated effects in adipose tissue of experimental animals, the importance of GH receptors in human adipose tissue is not fully elucidated at present although the available data indicate a functional role. However, GH is clearly involved in the regulation of visceral fat mass in humans. Acromegaly, a state of GH excess, is associated with decreased visceral fat while in GH deficiency there is an increase in visceral fat and in adults with GH deficiency, recombinant human GH replacement therapy results in adipose tissue redistribution from visceral to subcutaneous locations; however, the regulation of adipose tissue metabolism requires synergism with steroid hormones A direct demonstration of a regulation of the GH receptor in human fat cells has not yet been performed Thyroid hormone receptors. Thyroid hormones have multiple catabolic effects on fat cells as a result of interactions with the adrenergic receptor signal transduction system, and most of these interactions are also present in human fat cells There are data regarding the characterization of the nuclear T 3 receptor in human fat cells Although receptor regulation has not yet been demonstrated, there is little doubt that the thyroid hormone receptors are important for the function of human adipose tissue Further, no data are available on the correlation between visceral fat mass and thyroid hormone levels. Adenosine receptors. Adenosine behaves as a potent antilipolytic and vasodilator agent and can be considered as an autocrine regulator of both lipolysis and insulin sensitivity in human adipose tissue. Site differences in ambient adenosine concentration, perhaps controlled by blood flow, may also modulate adipose tissue metabolism 7. Adenosine content is higher in omental than in abdominal subcutaneous adipose tissue, but the receptor-dependent inhibition of lipolysis is, as indicated before , less pronounced in the former than in the latter depot However, despite strong antilipolytic effect of adenosine analogs, human adipocytes contain few adenosine type A l receptors, regardless of the fat depot considered According to Arner , the α2-, β l -,β 2 -, and β 3 -adrenoreceptors and receptors for insulin, adenosine, and glucocorticoids, as well as for PGE 2 , a potent antilipolytic agent with high affinity receptors identified in adipocytes , have a major functional role, as shown by relevant biological receptor-mediated effects, the presence of a receptor molecule, and receptor regulation. The receptors for GH, thyroid hormones, estrogen, and testosterone, as well as for acetylcholine and TSH, probably have an important functional role but complete evidence, indicated in the previous group of receptors, is not present so far; however, there is little doubt of a regulatory role. Genetic epidemiology: heritability and segregation analysis. Studies performed in individuals from families of French descent living in Quebec City [Quebec Family Study QFS ] allowed the estimation of the fraction of the phenotypic variance that could be attributed to the genetic and environmental factors among the obesity phenotypes or in the distribution of the adipose tissue, taking into account the BMI and amount of subcutaneous fat by the sum of the measurement of skinfolds in six different sites , lean body mass, fat mass, percentage of fat derived from underwater weighing, and visceral fat by CT , The residual variance corresponded to environmental factors, but some factors cultural, nongenetic could be transmitted from parents to descendents and sometimes were confounded by genetic effects Segregation analysis studies have recently concluded that visceral fat is similarly influenced by a gene with a major effect in the QFS and HERITAGE families , However, after adjustment of the visceral adipose tissue for the fat mass, the effect of the gene with the major effect was not more compatible with a mendelian transmission. These results suggested the presence of a pleiotropism: the gene with the major effect, identified by the fat mass , could similarly influence the amount of visceral fat Similar results were obtained with the same type of analysis in the HERITAGE cohort To test the hypothesis of a genetic pleiotropism, Rice et al. The results of this study Fig. These results have confirmed the presence of a genetic pleiomorphism and suggested the presence of genes affecting simultaneously the amounts of fat mass and visceral abdominal fat. Schematic representation of the genetic effects on total fat mass and visceral fat adjusted for the fat mass and on the co-variation between the two phenotypes Quebec Family Study, G 1 and G 2 represent the genetic effects specific for the total fat mass and visceral fat, respectively. E 1 and E 2 represent the specific effects of the environment on total fat mass and visceral fat, respectively. G 3 and E 3 indicate the genetic and environment effects common to both phenotypes. Pérusse et al. The interactions of the effects of genotype and environment evaluated in monozygotic twins, when the energy balance is manipulated, indicated that even though there were large interindividual differences in the response to excess or negative energy balance, there was a significant within-pair resemblance in response 96 , In effect, in response to overfeeding, there was at least 3 times more variance in response between pairs than within pairs for the gains in body weight, fat mass, and fat-free mass In relation to the response to the negative energetic balance, at least 7 times more variation was observed in response between pairs than within members of the same pair of twins, with respect to the same variables This intrapair similarity in the response to either excess or deficient energy balance is also observed in relation to the abdominal visceral fat Thus, the interaction between genotype and environment is important to consider in the study of the genetics of obesity since the propensity to fat accumulation is influenced by the genetic characteristics of the subject. Molecular genetics: association and linkage studies. Several candidate genes as well as random genetic markers were found to be associated with obesity as well as body fat and fat distribution in humans. The current human obesity gene map, based on results from animal and human studies, indicates that all chromosomes, with the exception of the Y chromosome, include genes or loci potentially involved in the etiology of obesity Initial findings from the QFS showed that significant but marginal associations with body fat were found with LPL and the α2-subunit of the sodium-potassium ATPase genes The Trp64Arg mutation of the β 3 -adrenergic receptor gene β 3 AR , prevalent in some ethnic groups, is associated with visceral obesity and insulin resistance in Finns as well as increased capacity to gain weight This mutation was also shown to be associated with abdominal visceral obesity in Japanese subjects, with lower triglycerides in the Trp64Arg homozygotes but not heterozygotes It has been suggested that those with the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue. On the other hand, Vohl et al. Previously, it was reported by the same group that apo-B gene Eco R-1 polymorphism appeared to modulate the magnitude of the dyslipidemia generally found in the insulin-resistant state linked with visceral obesity These studies are a demonstration of a significant interaction between visceral obesity and a polymorphism for a gene playing an important role in lipoprotein metabolism. When the genes related to the hormonal regulation of body fat distribution studied in the QFS families sex hormone-binding globulin, 3β-hydroxysteroid dehydrogenase, and glucocorticoid receptor genes were considered along with the knowledge that body fat distribution is influenced by nonpathological variations in the responsiveness to cortisol, it was shown that the less frequent 4. However, the association with abdominal visceral fat area was seen only in subjects of the lower tertile of the percent body fat level. The consistent association between the glucocorticoid receptor polymorphism detected with Bcl I and abdominal visceral fat area suggested that this gene or a locus in linkage disequilibrium with the Bcl I restriction site may contribute to the accumulation of abdominal visceral adipose tissue With respect to the linkage studies, only a few studies of body fat or fat distribution with random genetic markers or candidate genes have been reported using the sibling-pair linkage method. One of the few reported studies relative to the visceral fat mass was the evaluation of a sib-pair linkage analysis from the QFS between five microsatellite markers encompassing about 20 cM in the Mob-1 region of the human chromosome 16pp These results suggested to the authors that this region of the human genome contains a locus affecting the amount of visceral fat and lipid metabolism as also shown by the association studies indicated above. The other population and intrafamily association study used a polymorphic marker LIPE in the hormone-sensitive lipase gene, located on chromosome 19q In conclusion, despite the fact that the genetic architecture of obesity has just begun, the results obtained so far suggest that a great number of genes, loci, or chromosomal regions distributed on different chromosomes could play a role in determining body fat and fat distribution in humans. This reflects the complex and heterogeneous nature of obesity. The accumulation of adipose tissue in the abdominal region is at least partially influenced by genes, which becomes more evident as the number of involved genes are identified. The concept that adipocytes are secretory cells has emerged over the past few years. Adipocytes synthesize and release a variety of peptide and nonpeptide compounds; they also express other factors, in addition to their ability to store and mobilize triglycerides, retinoids, and cholesterol. These properties allow a cross-talk of adipose tissue with other organs as well as within the adipose tissue. The important finding that adipocytes secrete leptin as the product of the ob gene has established adipose tissue as an endocrine organ that communicates with the central nervous system. As already mentioned, LPL is the key regulator of fat cell triglyceride deposition from circulating triglycerides. LPL is found, after transcytosis, associated with the glycosaminoglycans present in the luminal surface of the endothelial cells. The regulation of LPL secretion, stimulated by the most important hormonal regulator, insulin, is related to posttranslational changes in the LPL enzyme, at the level of the Golgi cisternae and exocytotic vesicles, insulin possibly having a positive role in this secretory process Genes encoding LPL were not differentially expressed in omental when compared with subcutaneous adipocytes However, in very obese individuals omental adipocytes express lower levels of LPL protein and mRNA than do subcutaneous fat cells The regulation of LPL in obesity has been presented in the Section on correlations of abdominal visceral fat. With respect to the hormonal regulation of LPL, insulin and glucocorticoids are the physiological stimulators of the LPL activity, and their association plays an important role in the regulation of body fat topography. In effect, omental adipose tissue is known to be less sensitive to insulin, both in the suppression of lipolysis and in the stimulation of LPL However, when exposed to the combination of insulin plus dexamethasone in culture for 7 days, large increases in adipose LPL were observed because of increases in LPL mRNA Significant differences were observed between men and women. The increase in LPL in response to dexamethasone suggests that the well known steroid-induced adipose redistribution especially in the abdomen may be caused by increases in LPL, which would lead to a preferential distribution of plasma triglyceride fatty acids to the abdominal depot. Therefore, these data suggest that LPL is central to the development of abdominal visceral obesity On the other hand, catecholamines, GH, and testosterone in males reduce adipose tissue LPL Acylation-stimulating protein ASP. ASP is considered the most potent stimulant of triglyceride synthesis in human adipocytes yet described. Its generation is as follows Human adipocytes secrete three proteins of the alternate complement pathway: C3 the third component of the complement , factor B, and factor D adipsin , which interact extracellularly to produce a amino-terminal fragment of C3 known as C3a. Excess carboxypeptidases in plasma rapidly cleave the terminal arginine from C3a to produce the amino acid peptide known as C3a desarg or ASP, which then acts back upon the adipocyte, causing triglyceride synthesis to increase. As fatty acids are being liberated from triglyceride-rich lipoproteins and chylomicrons as the result of the action of LPL, ASP is also being generated and triglyceride synthesis increased concurrent with the need to do so. In human adipose tissue, in the postprandial period, ASP secretion and circulating triglycerides clearance are coordinated in accordance with the suggestion that ASP in sequence to LPL would have a paracrine autoregulatory role. The adipsin-ASP pathway, therefore, links events within the capillary space to the necessary metabolic response in the subendothelial space, thus avoiding the excess buildup of fatty acids in the capillary lumen. The generation of ASP is triggered by chylomicrons. While insulin decreases gene expression of C3, B, and adipsin, it enhances the secretion of ASP as expected from the concurrent action of LPL and ASP. However, more intensely and independent of insulin, ASP is capable of stimulating triglyceride synthesis in adipocytes and fibroblasts. Thus, from the reduced sensitivity to insulin in the suppression of lipolysis and stimulation of LPL by the omental adipose tissue, omental obesity may represent an example of impaired activity of the ASP pathway even if dysfunction of the pathway is a secondary feature. As a consequence, omental adipose tissue, as compared with subcutaneous fat tissue, would have a limited capacity to prevent fatty acids from reaching the liver, which may contribute to the abnormalities in metabolism observed in visceral obesity Cholesteryl-ester transfer protein CETP. Human adipose tissue is rich in CETP mRNA, probably one of the major sources of circulating CETP in humans. CETP promotes the exchange of cholesterol esters of triglycerides between plasma lipoproteins. In this way, the adipose tissue is a cholesterol storage organ in humans and animals; peripheral cholesterol is taken up by HDL species, which act as cholesterol efflux acceptors, and is returned to the liver for excretion , The few studies of circulating CETP in obesity have shown that activity and protein mass of CETP are both significantly increased in obesity, being negatively correlated with HDL cholesterol and the cholesteryl ester-triglyceride ratio of HDL2 and HDL3, thus exhibiting an atherogenic lipoprotein profile. Furthermore, there was a positive correlation with fasting plasma insulin and blood glucose, suggesting a possible link to insulin resistance — From an observation of Angel and Shen , it could be suggested that the CETP activity of omental adipose tissue is greatly increased in comparison with subcutaneous fat. Retinol-binding protein RBP. Adipose tissue is importantly involved in retinoid storage and metabolism. RBP is synthesized and secreted by adipocytes , the rate of RBP gene transcription being induced by retinoic acid The mRNA encoding RBP is expressed at a relatively high level in adipocytes with no difference between subcutaneous and omental fat cells There are no data regarding retinol mobilization from adipose stores in humans; however, in vitro studies with murine adipocytes showed that the cAMP-stimulated retinol efflux from fat cells was not the result of increased RBP secretion but instead due to the hydrolysis of retinyl esters by the cAMP-dependent hormone-sensitive lipase PAI-1 is a serine protease inhibitor and evidence suggests that it is a major regulator of the fibrinolytic system, the natural defense against thrombosis. It binds and rapidly inhibits both single- and two-chain tissue plasminogen activator tPA and urokinase plasminogen activator uTPA , which modulate endogenous fibrinolysis. The major sources of PAI-1 synthesis are hepatocytes and endothelial cells, but platelets, smooth muscle cells, and adipocytes are also contributors The increased gene expression and secretion of PAI-1 by adipose tissue contribute to its elevated plasma levels in obesity, presenting a strong correlation with parameters that define the insulin resistance syndrome, in particular with fasting plasma insulin and triglycerides, BMI, and visceral fat accumulation: omental adipose tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, and transforming growth factor-βl increased PAI-1 antigen production In a premenopausal population of healthy women with a wide range of BMI, there was a positive correlation of PAI-1 activity with CT-measured visceral fat area, independent of insulin and triglyceride levels. Weight loss confirmed this link. PAI-1 diminution was correlated only with visceral adipose tissue area loss and not with total fat, insulin, or triglyceride decrease Results from in vitro studies have shown that insulin — stimulates PAI-1 production by cultured endothelial cells or hepatocytes. Attempts to extrapolate these in vitro data to in vivo proved difficult. Acute 2-h hyperinsulinemia modulation of plasma insulin in humans did not affect PAI-1 levels, and hypertriglyceridemia from several origins was not always associated with increased PAI-1 levels In the same way, exogenous short-term insulin infusion with triacylglycerol and glucose failed to demonstrate elevations of PAI-1 The augmentation of PAI-1 by insulin probably requires concomitant elevation of lipids and glucose and perhaps other metabolites in blood, as suggested by the strikingly synergistic effects when Hep G2 cells are exposed to both insulin and fatty acids in vitro Accordingly, a hyperglycemic hyperinsulinemic clamp associated with an intralipid infusion for 6 h, to induce hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia, produced an increase in PAI-1 concentrations in blood for as long as 6 h after cessation of the infusion However, the extent to which elevation of any one constituent or any given combination of elevations is sufficient to induce the phenomenon has not yet been elucidated in insulin-resistant patients. Craig, B. Adaptation of fat cells to exercise: response of glucose uptake and oxidation to insulin. Stanford, K. et al. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis. Rosen, E. What we talk about when we talk about fat. Cell , 20—44 Tran, T. Beneficial effects of subcutaneous fat transplantation on metabolism. Enerback, S. The origins of brown adipose tissue. Article Google Scholar. Kharitonenkov, A. FGF as a novel metabolic regulator. Effects of stopping training on size and response to insulin of fat cells in female rats. Download references. The authors acknowledge funding from The Swedish Research Council, European Research Council, Swedish Diabetes Association, Swedish Foundation for Strategic Research, Strategic Diabetes Research Program at Karolinska Institutet, Stockholm County Council and Novo Nordisk Foundation. Department of Physiology and Pharmacology, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4a, Stockholm, SE 77, Sweden. Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4a, Stockholm, SE 77, Sweden. You can also search for this author in PubMed Google Scholar. Correspondence to Juleen R. Reprints and permissions. Exercise remodels subcutaneous fat tissue and improves metabolism. Nat Rev Endocrinol 11 , — Download citation. Published : 24 February Issue Date : April Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Journal of Science in Sport and Exercise Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Subjects Diabetes Fat metabolism Obesity Weight management. Access through your institution. Buy or subscribe. Relevant articles Open Access articles citing this article. The Effect of a 12 Week Mixed-Modality Training Intervention on the Cardio-Metabolic Health of Rotational Shift Workers Blake E. Collins , Tegan E. Hartmann … Melissa Skein Journal of Science in Sport and Exercise Open Access 24 November Fast synthesis of platinum nanopetals and nanospheres for highly-sensitive non-enzymatic detection of glucose and selective sensing of ions Irene Taurino , Gabriella Sanzó … Sandro Carrara Scientific Reports Open Access 30 October Change institution. Learn more. Figure 1: Exercise training remodels subcutaneous adipose tissue and improves glucose homeostasis. References Egan, B. Article CAS Google Scholar Wallberg-Henriksson, H. CAS PubMed Google Scholar Hawley, J.
Why is visceral fat worse than subcutaneous fat?	Rutten, MD, PhD, Department of Internal Medicine , Radboudumc Nijmegen, P. Although the cause-and-effect association has not been definitively established, the available evidence indicates that visceral fat is an important link between the many facets of the metabolic syndrome: glucose intolerance, hypertension, dyslipidemia, and insulin resistance In the same way, it was demonstrated that PAI-1 production was significantly correlated with that of tumor necrosis factor-α TNFα , emphasizing a possible local contribution of TNFα in the regulation of PAI-1 production by human adipose tissue Select Format Select format. Here's what to expect if your baby is larger-than-average. Adipocytes are both a source of and a target tissue of the cytokine TNFα, which is absent in the preadipocyte although it is expressed in the adipocyte.
What Is Subcutaneous Fat?	Although the health-promoting effects of exercise are largely ascribed to improvements in skeletal muscle insulin sensitivity, new data published in Diabetes suggest 'exercise-trained' subcutaneous adipose tissue might also have an important role in enhancing glucose homeostasis. This is a preview of subscription content, access via your institution. Journal of Science in Sport and Exercise Open Access 24 November Scientific Reports Open Access 30 October Egan, B. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. Article CAS Google Scholar. Wallberg-Henriksson, H. Contractile activity increases glucose uptake by muscle in severely diabetic rats. CAS PubMed Google Scholar. Hawley, J. Integrative biology of exercise. Cell , — Craig, B. Adaptation of fat cells to exercise: response of glucose uptake and oxidation to insulin. Stanford, K. et al. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis. Rosen, E. What we talk about when we talk about fat. Cell , 20—44 Tran, T. Beneficial effects of subcutaneous fat transplantation on metabolism. Enerback, S. The origins of brown adipose tissue. Article Google Scholar. Kharitonenkov, A. FGF as a novel metabolic regulator. Effects of stopping training on size and response to insulin of fat cells in female rats. Download references. The findings are published in the journal Nature Communications. Obesity and stress on the endoplamic reticulum cause inflammation through upregulation of GATA 3 and TRIP-BR2 in visceral fat. Credit: Chong Wee Liew. All body fat is not created equal in terms of associated health risks. Visceral fat is strongly linked to metabolic disease and insulin resistance, and an increased risk of death, even for people who have a normal body mass index. In previous studies, Chong Wee Liew, assistant professor of physiology and biophysics in the UIC College of Medicine, and his colleagues found that in obese humans TRIP-Br2 was turned-up in visceral fat but not in subcutaneous fat. When the researchers knocked out TRIP-Br2 in mice and fed them a high-calorie, high-fat diet that would make the average rodent pack on the grams, the knockout mice stayed relatively lean and free from insulin resistance and inflammation. The relationship between adipokines, metabolic parameters and insulin resistance in patients with metabolic syndrome and type 2 diabetes. J Int Med Res. Pou KM, Massaro JM, Hoffmann U, Vasan RS, Maurovich-Horvat P, Larson MG, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Njajou OT, Kanaya AM, Holvoet P, Connelly S, Strotmeyer ES, Harris TB, et al. Association between oxidized LDL, obesity and type 2 diabetes in a population-based cohort, the Health, Aging and Body Composition Study. Diabetes Metab Res Rev. Indulekha K, Anjana RM, Surendar J, Mohan V. Association of visceral and subcutaneous fat with glucose intolerance, insulin resistance, adipocytokines and inflammatory markers in Asian Indians CURES Clin Biochem. Utzschneider KM, Carr DB, Tong J, Wallace TM, Hull RL, Zraika S, et al. Resistin is not associated with insulin sensitivity or the metabolic syndrome in humans. Norata GD, Ongari M, Garlaschelli K, Raselli S, Grigore L, Catapano AL. Plasma resistin levels correlate with determinants of the metabolic syndrome. Eur J Endocrinol. Reilly MP, Lehrke M, Wolfe ML, Rohatgi A, Lazar MA, Rader DJ. Resistin is an inflammatory marker of atherosclerosis in humans. Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, Shimada A, et al. Correlation between serum resistin level and adiposity in obese individuals. Download references. JC wrote the manuscript, researched data, contributed to the discussion, reviewed and edited the manuscript, and takes responsibility for the contents of the article. SK wrote the manuscript, researched data including statistical analyses , contributed to the discussion, and reviewed and edited the manuscript. SS, YL, and HK advised on analyses and commented on drafts of the manuscript. contributed to the measurement of adipose tissue, and interpretation of the results. All authors read and approved the final manuscript. This work was supported by the Catholic Medical Center Research Foundation in the program year of B Department of Family Medicine, St. Department of Family Medicine, Uijeongbu St. Department of Radiology, College of Medicine, St. You can also search for this author in PubMed Google Scholar. Correspondence to Ju-hye Chung. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Kim, SH. et al. Relationship between deep subcutaneous abdominal adipose tissue and metabolic syndrome: a case control study. Diabetol Metab Syndr 8 , 10 Download citation. Received : 08 October Accepted : 25 January Published : 12 February Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Abstract Background The deep subcutaneous adipose tissue dSAT is closely related to the obesity-associated complications similarly to the characteristics of visceral adipose tissue VAT. Methods Abdominal computed tomography CT images were obtained in asymptomatic subjects subjects with MS and without MS. Conclusions We demonstrated that dSAT was associated with increased inflammation and oxidative stress, suggesting that dSAT is an important determinant of MS. Background Metabolic syndrome MS is a cluster of risk factors for type 2 diabetes and cardiovascular disease and is associated with increased mortality [ 1 ]. Methods Subjects A total of asymptomatic subjects patients with MS and subjects without MS were recruited from the outpatient clinics at St. Risk factor assessment and measurement of serum adipokine levels The anthropometric, clinical and laboratory investigations were performed on all subjects. Criteria for metabolic syndrome MS was defined according to the revised NCEP-ATP III criteria with an ethnic-specific cutoff point for abdominal obesity [ 16 ]. Measurement of abdominal adipose tissue by CT To assess abdominal fat distribution, approximately 4—5 continuous transverse images kV, mA, scanning time of 2 s, field of view of mm, and slice thickness 5 mm were obtained at the level of the L4—5 intervertebral space using a CT scanner LightSpeed, GE Healthcare, Milwaukee, WI. Full size image. Results Baseline characteristics of the study participants Table 1 summarizes the baseline characteristics of the study participants. Table 2 Partial correlation coefficients between metabolic risk factors and adipose tissue areas age-adjusted Full size table. Table 3 Multiple logistic regression analysis of metabolic syndrome Full size table. Discussion In this study, dSAT as well as VAT was associated with MS in both men and women. Conclusions In this study, we demonstrated that dSAT was associated with MS, increased inflammation, and oxidative stress, suggesting that dSAT is an important determinant of MS. References Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. Article PubMed Google Scholar Carr DB, Utzschneider KM, Hull RL, Kodama K, Retzlaff BM, Brunzell JD, et al. Article CAS PubMed Google Scholar Despres JP, Lemieux I. Article CAS PubMed Google Scholar Cancello R, Zulian A, Gentilini D, Maestrini S, Della Barba A, Invitti C, et al. 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Rights and permissions Open Access This article is distributed under the terms of the Creative Commons Attribution 4. About this article. Cite this article Kim, SH. Copy to clipboard. Contact us Submission enquiries: journalsubmissions springernature.
Access this article	However, the relative contribution at any individual visceral fat mass was quite variable. The Trp64Arg mutation of the β 3 -adrenergic receptor gene β 3 AR , prevalent in some ethnic groups, is associated with visceral obesity and insulin resistance in Finns as well as increased capacity to gain weight Obesity adds a generalized increase in lipid turnover sustained by an increased response to lipolytic agents, a reduced effect of antilipolytic hormones, and increased LPL activity, which is most likely due to chronic hyperinsulinemia and playing a role in maintaining excess body fat depots Table 3. Matsuda, B. Statins, which inhibit 3-hydroxymethyl-glutaryl-coenzyme A reductase HMG-CoA reductase to reduce LDL cholesterol levels, also have anti-inflammatory properties —

Subcutaneous adipose Subcutaneous fat and metabolism SAT is Plant-based supplement products homogeneous, as the fascia metaboism separates the deep Mwtabolism dSAT from fatt superficial SAT sSAT. The Subcutaneois of this study is Obesity and hypertension evaluate the sex-specific Subcutaneoux of metablism and dSAT with hepatic steatosis and Habit formation for athletes syndrome in overweight megabolism. We recruited individuals with a body mass index BMI greater than or equal to 27 and aged 55 to 81 years. Abdominal magnetic resonance imaging was performed around level L4 to L5 to measure visceral adipose tissue VATdSAT, and sSAT volumes. The amount of hepatic fat was quantified by MR spectroscopy. Men had significantly higher volumes of VAT In men, dSAT is associated with hepatic steatosis and adverse metabolic traits, such as lower HDL cholesterol levels, whereas in women with obesity sSAT shows a beneficial relation with respect to hepatic fat content.