Insulin sensitivity and adiposity -
Two ethnic groups with possibly the highest incidence in the world of obesity, insulin resistance, and type 2 diabetes are the Pima Indians in Arizona and the Micronesians of Nauru. In the case of the Nauruans, the degree of insulin resistance appears to correspond with their adiposity when compared to Caucasians Interestingly, it has been possible to compare US Pimas to an ethnically and genetically similar population in Mexico with less obesity and diabetes, and substantially different lifestyle; the greater insulin resistance of the US Pimas was accounted for in large part but not fully by their degree of obesity, suggesting that lifestyle, particularly the degree of physical activity, is an important independent contributor to insulin sensitivity There is not enough information at this time to determine the degree of genetic vs environmental contribution to ethnic differences, but data on diabetes from different ethnic groups in Mauritius and emerging genome-wide association studies eg, Ref.
Clearly, when long-term energy intake is greater than energy expenditure, adiposity will increase and vice versa. In childhood, some energy intake in excess of energy expenditure will be accounted for by growth, although the global increase in childhood obesity warns that excess energy intake must still be avoided.
Thus, positive energy balance will affect and increase the size of all adipose depots with the exception of BAT, but the variation in response to short-term change differs, with hepatic lipid changing most rapidly—even over days with overfeeding 85 or calorie restriction Preferential visceral adipose tissue loss with calorie restriction is metabolically desirable and is suggested to occur in the initial phase with modest weight loss by low-calorie diets [LCDs] or with very LCDs.
Longer-term moderate caloric restriction with greater weight loss was not associated with a preferential visceral fat loss reviewed in detail in Ref. Similarly, in response to 28 days of overfeeding and increased insulin resistance, nonobese men and women did not gain proportionally more visceral compared to sc fat Physical activity clearly increases energy expenditure and favors weight loss and reduced adiposity.
In fact, a high level of physical activity has been a strong characteristic of those overweight people who have lost substantial weight and maintained the loss, whereas the nature of the dietary regimen has been quite variable Moreover, calorie reduction without exercise in overweight sedentary subjects may result in just as much loss of lean as fat mass On the other hand, exercise alone has been only modestly successful in generating and maintaining weight loss or reduction in abdominal fat , However, long-term physical activity has an important influence on fat depot size The expected changes with the commencement of exercise training in sedentary obese individuals are summarized in Figure 2 97 , — A systematic review has indicated that exercise is particularly useful in reducing excess liver fat Furthermore, a systematic review of weight loss intervention studies, including LCD and very LCD with or without exercise or exercise alone, reported no preferential visceral vs abdominal sc fat loss from exercise beyond the magnitude of the weight loss achieved ; however, the type of exercise was not distinguished, and a recent meta-analysis suggests that aerobic rather than resistance exercise may be more beneficial in regard to visceral fat loss In the context of bariatric surgery, there is also evidence for an additive weight loss of 3—4 kg for subjects participating in exercise Representation of the effects of commencing exercise training in the obese person on various parameters in muscle, liver, and adipose tissue that could have a direct or indirect effect on insulin sensitivity.
Abdominal CT scan of an active Sumo wrestler right showing a large amount of sc fat with relatively little visceral fat compared with a person of similar adiposity left. Matsuzawa et al: Pathophysiology and pathogenesis of visceral fat obesity. Obes Res 3 suppl 2 S—S, , with permission.
Enhancement of insulin sensitivity by physical activity is quite rapid, occurring within 2 to 3 days 97 , , so this effect cannot be related to a change in adipose depot size although it could relate to intracellular lipid metabolism; see Section VI.
It is likely that change in adipose depot size and perhaps function, particularly hepatic and visceral, contribute to the long-term effects of exercise training on insulin sensitivity, although the relative importance of change in adipose depots vs the effect of exercise per se is unclear.
Irisin may be an important mediator of the metabolic benefits of exercise in humans, but there is a question whether the degree or consistency of the effect in humans is clinically meaningful , and the response of irisin to weight reduction from bariatric surgery is negative rather than positive , so further human studies are awaited with interest to clarify the clinical importance of this pathway.
Conventionalization of germ-free mice ie, colonization of their gut with a cecum-derived, distal microbial community results in a marked increase in body fat content, hepatic triglycerides, and insulin resistance within 10—14 days, despite no change in food intake or energy expenditure.
Furthermore, germ-free mice are protected from diet-induced obesity, glucose intolerance, and insulin resistance A number of possible mechanisms account for the observed resistance of germ-free mice to diet-induced obesity.
After conventionalization, the density of small intestinal villi capillaries doubles, and monosaccharide uptake into the portal blood is enhanced. Fat accumulation in the liver and adipose tissue is promoted by carbohydrate response element binding protein-mediated and SREBP-mediated hepatic and adipose tissue lipogenesis.
In comparison to their conventional counterparts, germ-free mice have increased levels of fasting-induced adipose factor FIAF , a circulating lipoprotein lipase LPL inhibitor, whose expression is normally selectively suppressed in the gut epithelium by the microbiota. The suppression of LPL activity results in reduced uptake of fatty acids and triglyceride accumulation in adipocytes.
FIAF also induces expression of PPAR-γ coactivator-1α, a key coactivator of nuclear receptors and enzymes involved in fatty acid oxidation. In addition, germ-free mice show increased fatty acid oxidation in liver and muscle, mediated by increased levels of phosphorylated AMPK and its downstream targets acetylCoA carboxylase, carnitine-palmitoyl transferase Therefore, germ-free animals are protected from diet-induced obesity by 2 complementary, but independent, mechanisms that result in decreased fatty acid storage: 1 elevated levels of FIAF; and 2 increased AMPK activity.
In contrast to the protection against obesity conferred by a microbe-free gut, in animal models of obesity, an altered microbiota composition has been associated with the development of obesity, insulin resistance, and diabetes through several mechanisms.
In animals fed an obesogenic diet, there is an alteration in the composition and functional properties of the gut microbiota, inducing enrichment in genes enabling energy harvest from otherwise indigestible components of the diet — Data from human studies investigating alterations in the composition of the gut microbiota in obesity have been generally consistent with animal models, but findings are more heterogeneous, likely related to the complexity of human lifestyle compared with a controlled experimental animal model — Alterations in gut microbiota in obesity can result in altered fatty acid metabolism and composition in adipose tissue and liver in mice — and may also modulate gut-derived peptide secretion including peptide YY and glucagon-like peptide 1 GLP-1 secretion, impacting on gut transit time, energy harvest, and satiety , These animal data demonstrate that gut microbiota modulate energy homeostasis and adiposity through numerous mechanisms including energy harvest from the diet, energy storage as triglyceride, energy expenditure through fatty acid oxidation, LPS-induced chronic inflammation, and gut-derived peptide secretion.
However, a causal relationship between gut microbiota and the development of obesity in humans remains to be proven, and it is not clear that gut microbiota would influence the distribution of lipid between different depots.
Men and women differ in the incidence of obesity, fat deposition patterns, utilization of fat as a metabolic fuel, serum lipid levels, genetic determination of metabolism-related genes, and health consequences of obesity.
These differences may reflect evolved adaptive differences that stem from the gender differences in reproductive costs Women of all ethnicities and cultures have greater adipose stores than men, even after correcting for BMI, and this increased adiposity is present from birth, with female babies having greater sc fat than males for all gestational ages Women have greater adipose stores in thighs and buttocks, with males more likely to have abdominal adiposity.
Furthermore, premenopausal women have a greater proportion of their abdominal fat in sc depots compared to males, with males having more visceral fat for all values of BMI This distribution of fat changes during the menopause transition; a longitudinal study using abdominal MRI to assess changes in fat depots through menopause showed no weight gain or change in BMI; however, both abdominal sc and visceral fat increased, with no change in the relative distribution of fat in the abdomen It has been suggested that estrogen depletion in the postmenopausal period may result in the increased deposition of body fat in the intra-abdominal region because administering hormone replacement therapy to postmenopausal women prevented an increase in abdominal fat Increased fatness, regardless of how measured, is associated with reduced peripheral insulin sensitivity.
Despite women having more body fat than men, insulin sensitivity in women appears to be less affected by the amount of body fat. Increases in body fat among women are associated with smaller decreases in insulin sensitivity compared to men , and in lean women there may be no relation between adipose depots and insulin sensitivity Women appear to be more physiologically geared to using fat as a metabolic fuel under conditions of sustained increased demand , whereas men rely relatively more on glucose and protein metabolism.
After feeding, fatty acid uptake is higher in abdominal adipose tissue relative to gluteal or femoral in both men and women.
However, in women, most of the fatty acid uptake in abdominal adipose tissue is into sc fat, whereas in men a larger proportion goes into visceral fat. Turnover of visceral fat is higher in men compared with women; fatty acid uptake into this depot in the postprandial period is approximately 7-fold higher in men than in women Men have greater rates of both lipolysis and lipogenesis in visceral fat compared with women, possibly due to fewer α-adrenergic receptors in this fat depot.
Adrenergic stimulation increases splanchnic fatty acid release in men but not in women, suggesting that the effects of visceral fat on health may differ between the sexes as well LPL is an enzyme that facilitates FFA uptake, and premenopausal women have lower activity of this enzyme in their intra-abdominal tissue than men In men, abdominal fat is an important adipose tissue depot regulating muscle sympathetic nerve activity, whereas in women, despite higher total body fat, this relationship is absent Lean and obese women have double the amount of IMTG as matched men , Roepstorff et al and others have shown a net reduction in IMTG during prolonged submaximal exercise only in women.
DAGs and ceramides have not been shown to be different in women and men , but further studies are required. Leptin and insulin are the only circulating hormones that act as appetite-suppressing signals. Leptin concentrations are more reflective of sc fat, whereas insulin levels are more reflective of visceral fat Because these 2 fat stores differ between the genders, leptin is better correlated with total adipose mass in women, and insulin is more correlated with total fat stores in men Fat is linked to reproduction through leptin.
Serum leptin concentration displays some persistent sex differences that begin even before birth. Circulating serum levels are higher in pregnancies where the fetus is female Females have higher levels at birth, and this difference persists throughout life.
These differences cannot be fully accounted for by differences in total adipose tissue women have higher levels of leptin for any given amount of fat mass or by relative amounts of adipose tissue in sc and visceral depots and may be mediated by primary genetic effects on leptin production or gonadal hormones.
As discussed in Section IV. When given therapeutically, oral estrogen, compared with transdermal estrogen, may cause a relative increase in adiposity and reduction in muscle mass apparently due to high concentrations of estrogen in the portal vein inhibiting IGF-I production Normal T levels favor muscle maintenance and limit fat mass as evidenced by increased fat mass and reduced muscle mass with androgen deprivation therapy; this impairs insulin sensitivity and increases diabetes incidence, although there is probably little increase in intra-abdominal fat , ; moreover, T therapy in men with T deficiency improves adiposity, insulin sensitivity, and cardiovascular risk profile GH deficiency also reduces muscle and increases fat mass, especially central fat, resulting in impaired insulin action.
GH therapy, while improving adiposity, does not improve insulin sensitivity, likely due to GH's direct inhibition of insulin action , As a result, there is no clear increase or decrease in risk of diabetes from GH therapy in GH-deficient adults Cortisol excess is well recognized for its ability to increase central adiposity and gluconeogenesis and impair insulin action, but Cushing's syndrome is relatively uncommon.
However, there has been great interest in the role of 11β-hydroxysteroid dehydrogenase, which converts inactive cortisone to active cortisol in tissues, including adipose tissue and liver, with data on cortisol metabolites, suggesting that this pathway is overactive in obesity.
Such overactivity could accentuate central adiposity, lipid synthesis, dyslipidemia, inflammation, and insulin resistance 10 , and there is evidence, mainly in animals but also in humans, that inhibiting or genetically deleting this enzyme can remediate each of these abnormalities in obesity , Although frank hyper- and hypothyroidism are associated with alterations in adiposity, whether more subtle changes in thyroid hormones are associated with insulin resistance, obesity, and the metabolic syndrome is controversial; a detailed discussion is beyond the scope of this review.
In some studies, humans with TSH values at the upper end of the normal range have higher BMI, higher triglyceride levels, and a greater chance of being diagnosed with the metabolic syndrome compared to individuals with lower TSH values An association between increasing TSH and waist circumference in overweight and obese women has also been demonstrated However, other studies have failed to confirm a significant effect of TSH elevation subclinical hypothyroidism on the risk of development of the metabolic syndrome in humans.
A number of medications have been shown to affect insulin sensitivity, with the majority doing so indirectly via changes in adiposity Table 5. Two possible exceptions are metformin and nicotinic acid.
Metformin is a biguanide drug, which is thought to predominantly improve insulin sensitivity in liver and, to a lesser extent, muscle via activation of AMPK Nicotinic acid causes insulin resistance probably by rebound elevation of FFA Medications That Significantly Affect Adiposity Excluding Weight Loss Drugs.
Because the role of bariatric surgery has very recently been reviewed in this journal , we will not deal with this subject in detail, but various bariatric procedures generate improvements in insulin sensitivity and glycemia in diabetic subjects associated with weight and adipose tissue loss, although there seems to be little information on relative loss of adipose tissue vs lean mass or differential reduction of different adipose depots.
It has been suggested that the improvement in insulin sensitivity may be disproportionate to changes in adiposity, at least for some procedures, and that altered secretion of gut hormones could be an important contributor to improved insulin secretion and insulin sensitivity Human lipodystrophy syndromes are comprised of a heterogeneous group of congenital and acquired disorders.
Most are characterized by a partial or near-complete absence of sc adipose tissue, but a relative increase in visceral fat; however, some have a loss of all adipose tissue, including visceral. They also have reduced leptin and adiponectin levels.
Clearly, the lack of adipose tissue storage capacity and favorable adipokines is of overriding importance because cases of lipodystrophy with absent visceral fat are not protected from the adverse consequences of lipodystrophy One form of lipodystrophy that has become increasingly common is HIV-related lipodystrophy , ; as with most other forms of lipodystrophy, there is a loss of sc fat, but a relative increase in visceral fat Figure 4 HIV lipodystrophy is associated with a substantially increased diabetes risk and an increase in cardiovascular events commensurate with the adverse metabolic profile, particularly lipids Fortunately, the syndrome, which was associated with earlier antiviral agents, especially protease inhibitors, is less commonly seen with newer antiviral agents that have been screened for these adverse metabolic effects A diagrammatic illustration of changes over time in central fat, limb fat, and lean mass in subjects with HIV AIDS commenced on older antiviral regimens including protease inhibitors.
Mallon et al. AIDS —, , with permission. MSL is a rare condition associated with adenomatous change in upper body sc fat and in a way represents the converse of the lipodystrophies.
Observations in MSL patients include improved insulin sensitivity , accompanied by decreased lipid in leg and liver , increased circulating adiponectin, decreased adipocyte size, and adipose tissue mRNA expression of proinflammatory cytokines compared with matched obese individuals without the condition.
Although total adiposity and adipose tissue distribution are important determinants of insulin resistance and type 2 diabetes, the size of adipocytes within adipose tissue depots also plays a contributing role.
This is illustrated in Pima Indians, in whom the presence of anatomically larger sc adipocytes is a better predictor of the onset of type 2 diabetes than the presence of obesity alone Similarly, individuals from southeast Asia, where there is a high prevalence of type 2 diabetes, have a lower number of adipocytes and increased adipocyte size in addition to an increase in the relative amount of visceral fat.
This may account for the increase in metabolic disease in Asians compared with Caucasians at the same level of BMI In adult humans, adipose tissue expansion occurs as a result of adipocyte hypertrophy and the recruitment and proliferation of preadipocytes adipogenesis During the development of obesity, the initial enlargement of adipocytes triggers the production of a number of paracrine adipogenic growth factors, resulting in the proliferation of new fat cells—that is an increase in fat cell size precedes an increase in fat cell number — Therefore, variations in adipocyte size may be related to a genetically or otherwise determined ability for adipogenesis—if adipogenesis is impaired during positive energy balance, then existing adipocytes continue to undergo hypertrophy to store excessive energy.
It has recently been shown that a low generation rate of new adipocytes associates with adipose hypertrophy, whereas a high generation rate of new adipocytes associates with the more benign adipose hyperplasia Increased adipocyte size correlates with serum insulin concentrations, insulin resistance, and increased risk of developing type 2 diabetes — Furthermore, adipocyte hypertrophy is associated with inflammation, with the proinflammatory factors IL-6, TNF-α, and CRP being positively correlated with adipocyte size — Conversely, the anti-inflammatory factor adiponectin is inversely correlated with adipocyte size Hypertrophic fat cells display distinct differences in gene expression and are more prone to cell death in response to mechanical stress, with subsequent inflammation, when compared with small adipocytes In contrast, the presence of more small adipocytes has a beneficial impact on metabolism.
PPAR-γ agonists improve insulin sensitivity and are an effective therapy in type 2 diabetes because they promote the recruitment and proliferation of small adipocytes, as well as decreasing the ratio of visceral to sc adipose tissue — Severely obese individuals with a healthy metabolic profile have smaller adipocytes and increased circulating adiponectin than obese individuals with adverse metabolic features Table 2.
If this hypothesis were correct, then individuals with a reduced capacity to generate new adipocytes would be susceptible to metabolic disease at a lower level of body fat than individuals with better lipid-storing potential Increased adiposity is associated with accumulation of macrophages in both visceral and sc fat 58 , ; moreover, increased LPS absorption from the gut related to changes in microbiota can activate immune cells Thus, in rodents inflammation is clearly important in generating insulin resistance , So could the degree of inflammation, rather than the level of tissue lipids, be the critical factor in human insulin resistance?
Several studies would suggest that this is not the case. Obese insulin-resistant subjects have higher CRP levels than obese insulin-sensitive subjects, but the obese insulin-sensitive have significantly higher CRP than a nonobese group with similar insulin sensitivity Moreover, insulin resistance may appear in relatives of type 2 diabetes patients without evidence of inflammation In support of this argument are studies that administered anti-inflammatory agents to obese diabetic and nondiabetic individuals and assessed the effect on insulin sensitivity, secretion, and glycemic control Table 6.
Specifically, clinical trials that studied the effect of TNFα inhibition — found no effect on insulin sensitivity by iv insulin tolerance test , HOMA-IR , , or hyperinsulinemic-euglycemic clamp Inconsistent improvements in insulin sensitivity with TNFα inhibition have been seen in patients with inflammatory arthritidies , with a tendency for greater improvement in those with more severe disease; but if there was a benefit, it is unclear whether it was a direct effect of TNFα inhibition or an indirect effect of disease improvement.
The Effect of Anti-Inflammatory Agents on Glucose Homeostasis in Patients With the Metabolic Syndrome. Inhibition of IL-1 receptor by IL-1r antagonist in obese type 2 diabetic or nondiabetic men and women also did not affect insulin sensitivity by HOMA-IR, hyperinsulinemic-euglycemic clamp, or insulin sensitivity index.
Studies of salicylate administration in overweight and obese diabetic — and nondiabetic , patients showed improved glycemia , , with a concomitant increase in adiponectin and reduction of circulating FFA , It was suggested that insulin sensitivity had been improved, but the elevation of insulin levels mainly related to reduced clearance seemed to fully explain the increased glucose disposal during hyperinsulinemia , Similarly, in nondiabetic obese subjects, it was suggested that insulin sensitivity was improved based on a HOMA-IR C-peptide calculation However, if HOMA-IR had been calculated in the usual manner with insulin levels , there would have been no improvement One way in which this apparent conflict between animal and human data could be reconciled is an important influence on insulin signaling by the nuclear factor κB NFkB pathway Figure 5.
This pathway is present in muscle and liver as well as immune cells and can be activated by saturated fatty acids , probably in conjunction with the hepatokine Fetuin A , by acting on TLR4 see Section VI.
as well as via circulating inflammatory molecules. Also, deletion of TLR2 protects against hepatic insulin resistance in mice A diagrammatic representation of factors influencing the accumulation of adipose tissue and resulting effects on insulin-responsive tissues in the lean A and obese B states beyond effects via the Randle cycle.
FFA supply may impact on insulin signaling via DAGs, ceramide, and PKCs via TLRs and NFkB. The influence of fat depots on insulin sensitivity has close connections with the levels and activity of adipose tissue and liver-derived hormones, although the cause and effect relationships and mechanisms involved in humans await further clarification Table 7.
Both leptin and adiponectin activate AMPK and increase fat oxidation but are otherwise different in their actions Figure 5. IL Acute release from exercising muscle likely to enhance insulin sensitivity. Low level chronic elevation may contribute to insulin resistance.
Leptin, which is secreted more from sc than visceral fat , reduces appetite and increases metabolic rate The cause of leptin resistance is poorly understood, but it may involve impairment of receptor signaling and reduced passage across the blood-brain barrier One possibility is that expanded adipose tissue sends a humoral message that inhibits leptin action; this seems unlikely because leptin administration is highly effective in very obese leptin-deficient animals or humans , A second possibility is that a leptin-resistance mechanism is integral to the genetic predisposition to obesity; this also seems unlikely to be a common mechanism because diet-induced adiposity induces leptin resistance in rodents Adiponectin, especially the high molecular weight form, also preferentially secreted by sc fat , is anti-inflammatory and has protective effects in relation to atheromatous cardiovascular disease , , , This hormone also fails to compensate for adiposity because adiponectin levels, including the high molecular weight form, fall with increasing adiposity.
However, the likely importance in regard to insulin sensitivity is attested in adiponectin knockout and transgenic animals and the already mentioned dependence of the insulin-sensitizing effects of thiazolidinediones on increased adiponectin levels IL-6 is released from muscle in response to exercise and has an important role in mobilizing myocyte fatty acids and hepatic glucose output to supply energy to muscle , but in the nonexercising state, adipose tissue is thought to be an important source; levels are modestly elevated in obesity and reduced by exercise training.
Although it has been suggested that IL-6 may contribute to insulin resistance by increasing fatty acid supply or by contributing to inflammation via CRP release , infusion of IL-6 in humans increases rather than decreases insulin-mediated glucose disposal Thus, IL-6 does not seem to be an important player in human insulin resistance.
AFABP is produced in adipocytes and, to a lesser extent, in macrophages , and its blockade or disruption benefits insulin resistance, dyslipidemia, and liver steatosis in obese or fat-fed animals In humans it has also been elevated in and predictive of type 2 diabetes and the metabolic syndrome — and predictive of liver inflammation and fibrosis in nonalcoholic fatty liver disease ; moreover, AFABP gene variants are associated with obesity and insulin resistance Thus AFABP, either by enhancing availability of fatty acids to tissues or as part of a macrophage inflammatory response , is a potentially important player in regard to insulin resistance and the metabolic syndrome Retinol binding protein 4, secreted from adipose tissue and liver, has been proposed as an important contributor to insulin resistance , but a number of subsequent human studies have not supported this , , , ; also, there has been concern about whether different assays give different circulating levels.
At this time, its role in insulin resistance is uncertain. FGF 21 is a member of the FGF superfamily and is produced in liver, white and brown adipose tissue, and pancreas , Its circulating levels are increased in obesity and insulin resistance in animals and humans and in response to fasting or a ketogenic diet in animals.
Pharmacological induction of FGF 21 activity would seem to have therapeutic possibilities in relation to type 2 diabetes and the metabolic syndrome. Fetuin A is a glycoprotein secreted from the liver that is associated with insulin resistance in humans , and has been shown to stimulate the production of inflammatory cytokines from adipocytes and macrophages as well as suppressing adiponectin levels Recently, Pal et al showed that Fetuin A is an endogenous ligand for TLR4 and presents circulating fatty acids to TLR4.
They showed elevated circulating Fetuin A levels in humans with type 2 diabetes and mice with genetic or diet-induced obesity and insulin resistance; moreover, deletion or knockdown of either Fetuin A or TLR4 protected the mice from insulin resistance. The effects were of sufficient magnitude to indicate that impaired muscle insulin action must have been involved, and they showed reduced insulin-stimulated 2-deoxyglucose uptake in isolated skeletal muscle cells from wild-type high-fat-fed animals that was not evident in the 2 knockdown groups; whether these effects were due to an indirect action via circulating cytokines or a direct effect on the TLR4-NFkB pathway in muscle is at present unclear.
This hepatokine would seem to have the potential to contribute significantly to obesity-induced insulin resistance in humans. Lipocalin-2, a member of the lipocalin family, is a kDa secretory glycoprotein that acts as a chaperone to bind and transport various lipophilic substances.
It has been implicated in diverse functions such as apoptosis, innate immunity, iron delivery, and more recently as a regulator of metabolic and inflammatory pathways. Lipocalin-2 is expressed by adipocytes and many other tissues including liver, lung, thymus, kidney, small intestine, mammary gland, neutrophils, and macrophages.
Expression is induced by proinflammatory stimuli including LPS, TNF-α, hyperglycemia, IL-1β, and IL, and increased levels are found in acute and chronic inflammatory conditions, such as infection including chronic hepatitis C; Ref.
Lipocalin-2 levels are increased in obese animal models together with increased expression in adipose tissue and obese human subjects, as well as subjects with polycystic ovary syndrome Levels correlate positively with measures of adiposity BMI, WHR, waist circumference , components of the metabolic syndrome, as well as insulin resistance as measured by HOMA-IR and the inflammatory marker CRP.
Association with HOMA-IR remains significant even after adjustment for age, gender, and BMI. Both obese animal models and humans treated with the PPAR-γ agonist, rosiglitazone, reduced lipocalin-2 expression and circulating levels, and this correlated with improved insulin sensitivity A recent cross-sectional study in a Chinese population showed a strong correlation between lipocalin-2 levels and impaired glucose tolerance and type 2 diabetes independent of possible confounders Addition of exogenous recombinant lipocalin-2 to obese animal models increased glucose production in hepatocytes, suggesting that it may have a causal role in insulin resistance and hyperglycemia.
Animal models of atherosclerosis have increased levels of lipocalin-2, and levels are high in human atherosclerotic plaques. Furthermore, lipocalin-2 levels correlate with visceral fat in patients with coronary artery disease and predict the severity of coronary artery disease, and levels in patients with atherosclerosis predict mortality in a 4-year study This protein may act at the interface of lipid metabolism, inflammation, insulin resistance, and atherosclerosis in obesity states.
Resistin is a member of a family of closely related peptides. It is secreted preferentially by intra-abdominal fat but also expressed in leukocytes, macrophages, spleen, and bone marrow and has been shown in animals to cause hepatic insulin resistance and to be a potential contributor to cardiovascular disease , , but its role in human insulin resistance is unclear at this time Visfatin was originally identified from visceral fat and is up-regulated in obesity, but it may be the product of macrophages in adipose tissue; it is also produced by leukocytes, myocytes, and hepatocytes.
The contribution, if any, of visfatin to human insulin resistance is uncertain Omentin is another adipokine preferentially secreted by visceral fat but also expressed in heart, lungs, ovary, and placenta with lower circulating levels in obesity and insulin resistance; because it has insulin-sensitizing and anti-inflammatory effects in animals, its impaired secretion is also a potential contributor to insulin resistance, but further work is needed to clarify its importance in humans CRP is an acute phase reactant produced by the liver, which is substantially elevated in acute inflammatory or infective states.
However, mild chronic elevation of CRP is seen in human obesity and has been strongly associated with cardiovascular risk Although also associated with insulin resistance , its pathogenic contribution to reduced insulin sensitivity has been unclear.
Recently, Tanigaki et al have shown that CRP transgenic mice demonstrate muscle but not liver insulin resistance, apparently due to an effect on muscle microvascular endothelium attenuating insulin-stimulated skeletal muscle blood flow. This effect is evident before, and is therefore not due to, a modest increase in adiposity in the transgenic animals.
Although CRP levels were not grossly elevated in this study, it remains to be determined how important the contribution of the mild elevation of CRP in human obesity is to impaired insulin action see also Section VI. Vitamin D 25OHD insufficiency has now been linked with a variety of adverse health outcomes beyond the area of bone and calcium; these include type 2 diabetes risk with evidence for impairment of both insulin secretion and action Increased adiposity may cause excess vitamin D storage in fat depots and reduce its biological availability.
Thus, there is the potential for obesity to compound or interact with vitamin D insufficiency and contribute to insulin resistance. A recent report from the National Health and Nutrition Examination Survey showed an additive but not synergistic effect of abdominal and overall obesity and 25OHD insufficiency on insulin resistance by HOMA-IR.
The importance or the magnitude of this effect of 25OHD on insulin sensitivity needs further evaluation. Randle et al first demonstrated that increased fatty acid supply and oxidation could inhibit glucose oxidation by mechanisms particularly involving pyruvate dehydrogenase.
Although this mechanism may contribute to impairment of insulin-mediated glucose disposal, it does not account for the well-established inhibition of GLUT4 translocation and glucose transport, which characterize insulin resistance in animals and humans 94 mechanisms by which fatty acids may impair glucose transport are considered below.
It is also relevant that circulating triglycerides with lower carbon number and double bonds are associated with insulin resistance and epidemiologically with increased diabetes risk ; it is unclear whether this is a causative relationship, but it is possible that corresponding triglyceride-derived DAGs or ceramides could have a greater impact on insulin signaling.
In animal studies, feeding a high-fat diet to rats increases liver lipid and causes reduced hepatic insulin sensitivity after 3 days.
By 3 weeks, there is increased lipid in muscle and impaired muscle insulin action This insulin resistance due to high-fat feeding can be reversed in less than 24 hours by fasting, exercise, or carbohydrate feeding , On the other hand, choline deficiency can greatly increase hepatic lipid without a reduction in glucose tolerance or insulin sensitivity, with data suggesting that this is related to shunting of FFAs into triglyceride stores Similarly, in overweight humans, calorie restriction coupled with improvement in insulin sensitivity was not accompanied by reduction in triglycerides in skeletal muscle Thus, acute caloric restriction could reduce tissue availability especially in liver and muscle of these active metabolites before a significant depletion of triglyceride stores.
Conversely, fatty acid conversion to DAGs, etc. Athletes may be very good at holding their fatty acids in IMTG stores in muscle until commencing exercise.
Both ceramides and DAGs have been reported to impair insulin action in muscle and liver cells. Ceramides accumulate in cells in response to multiple stress stimuli including inflammation and oxidative stress.
In muscle, ceramides mediate insulin resistance through inhibition of Akt signaling, potentially via protein phosphatase 2 and PKCζ-dependent pathways , Ceramides are also linked to mitochondrial dysfunction, further increasing ectopic deposition of lipids capable of mediating insulin resistance Studies in insulin-resistant and insulin-sensitive humans have analyzed lipids in muscle and liver tissues taken by biopsies or during surgery in order to shed light on the lipid that aligned with insulin resistance Table 8.
In muscle, elevated DAG and ceramide , , were reported in obese diabetic, obese nondiabetic, and insulin-resistant lean individuals compared with insulin-sensitive lean individuals, but this was not confirmed in other studies , Table 8.
As mentioned above, ceramides are in flux with other sphingolipids, of which sphingomyelin and glucosylceramide were not reported to accumulate in muscle of insulin-resistant humans Table 8.
Interestingly, when obese insulin-sensitive women were compared with obese insulin-resistant women, some ceramide, but not DAG, species were significantly elevated in the insulin-resistant group Table 2 , emphasizing the potential importance of ceramide species to the underlying insulin resistance phenotype, irrespective of obesity.
Interestingly, a small randomized study of weight loss intervention in obese men and women found an improvement in insulin sensitivity with either calorie restriction or exercise with a concomitant decrease in all DAG species in muscle, but the change in ceramide species was intervention-dependent, with 6 of 8 measured species decreasing with exercise and 3 decreasing and 1 increasing with calorie restriction , suggesting that different ceramide species may be involved in the insulin-sensitizing effect of calorie restriction and exercise and that specific ceramide species may be harmless to insulin sensitivity.
Further lifestyle intervention studies in humans are warranted. Lipid Moieties Implicated in Insulin-Resistant Compared to Insulin-Sensitive Humans in Skeletal Muscle and Liver.
Hepatic ceramides are suggested to play a role in the progression of fatty liver disease to steatohepatitis, but their role in the preceding noninflammatory fatty liver is debated — Unlike ceramide, DAG accumulation in liver was suggested to play a role in hepatic insulin resistance Table 8.
Two recent studies in severely obese individuals have reported significant associations between liver DAG and suppression of endogenous glucose output during hyperinsulinemic clamp or the surrogate HOMA-IR , but no association with ceramide accumulation. Limitations of cross-sectional studies in humans that likely contributed to the conflicting findings include focus on accumulation of an isolated lipid class or incomplete data , use of different assays to measure different lipids, and when lipid species within classes were reported, detection of different species in different laboratories that complicated the comparison between sets of data.
Most importantly, lipid metabolism in cells is highly compartmentalized, and in most studies in humans lipid analyses were performed on extracts from whole tissues. The metabolic syndrome or insulin resistance syndrome has been variously defined 4 , 5 , but represents an association between central adiposity population-specific waist circumference , insulin resistance, dysglycemia, hypertension, and dyslipidemia, particularly elevated triglycerides and low HDL cholesterol.
Various additional features have been proposed, most notably nonalcoholic fatty liver disease 5. It has been used as a concept to advance research and understanding of the relationship of metabolic disturbances with cardiovascular disease , but also as a medical diagnosis in individual management.
Much has been written about the usefulness of the metabolic syndrome as a diagnosis. It appears to signify a doubling or more of diabetes risk even when blood glucose levels are normal 5 , , but whether it carries cardiovascular prognostic information of more value than can be derived from its component criteria is controversial 5 , — Because this issue has been well reviewed eg, Ref.
Because insulin resistance is accompanied by hyperinsulinemia until the development of diabetes , there will be increased insulin-stimulated hepatic lipogenesis compounding the contribution of excess fatty acid availability to the liver and the general accumulation of ectopic lipid.
Hepatic steatosis and insulin resistance, as well as abdominal sc and visceral fat, are closely associated with dyslipidemia , , particularly increased secretion of very low-density lipoprotein VLDL 1 and apolipoprotein B , with hepatic lipid content being the strongest predictor ; but the hypertriglyceridemia is also contributed to by severely impaired clearance of triglyceride-rich VLDL particles , the latter associated with increased plasma levels of apolipoprotein C III, which is involved in VLDL catabolism Hepatic steatosis and insulin resistance are also associated with low HDL cholesterol and small, dense low-density lipoprotein particles related to increased action of hepatic lipase and cholesterol ester transfer protein 5 , Moreover, insulin resistance is also associated with intestinal triglyceride-rich lipoprotein overproduction in part related to up-regulation of microsomal triglyceride transfer protein the key protein involved in intestinal lipoprotein assembly and enhanced intestinal enterocyte de novo lipogenesis by ERK-mediated up-regulation of SREBP-1c Thus, multiple mechanisms link insulin resistance to the characteristic hypertriglyceridemia and low HDL of the metabolic syndrome.
There is controversy as to the importance of inflammation in the generation of insulin resistance in humans, but there is no doubt of the association of obesity with inflammation , , and inflammation is a well-established marker of, and likely contributor to, cardiovascular disease , so this would seem a second candidate pathway to adverse cardiovascular outcomes.
In addition, the possible role of perivascular fat has already been discussed Section III. Obesity also contributes to cardiovascular risk by raising blood pressure by mechanisms that appear to be predominantly related to neurohormonal activation but are incompletely understood Sodium retention and increased sympathetic nervous activity due to hyperinsulinemia have been implicated, and elevation of portal vein fatty acids may aggravate the latter effect , whereas modest hyperaldosteronism may result from adipose tissue-derived angiotensinogen The importance of this issue is evidenced by the increased medication required by obese hypertensive subjects and the benefit of weight loss in management of hypertension, at least when the weight loss is substantial Nevertheless, the contribution of insulin resistance to hypertension may be less than to other components of the metabolic syndrome Endothelial dysfunction is another likely contributor to cardiovascular risk.
This was first related to type 2 diabetes and associated with reduced nitric oxide availability but has subsequently been linked more with central adiposity, low-grade inflammation, and insulin resistance , Finally, altered adipokine secretion is another likely contributor to cardiovascular risk because central adiposity and insulin resistance are associated with reduced adiponectin levels, and this adipokine has been shown in humans to correlate inversely with arterial disease and in mouse transgenic studies to have significant antiatherogenic properties In summary, the various adipose depots in humans appear to affect insulin action first by influencing the tissue supply of fatty acids and their metabolically active derivatives, DAGs, LCACs, and ceramides.
When considering the pathogenic contribution of liver fat to insulin resistance, it is important to remember that the lipogenic action of insulin is not impaired in insulin resistance, so the compensatory hyperinsulinemia would overstimulate lipogenesis; thus increased hepatic lipid could be a consequence as well as a cause of insulin resistance.
Visceral fat appears capable of contributing to insulin resistance 3 , in part by a poorly understood down-regulation of adiponectin secretion, and its surgical removal benefits insulin action in rats 48 , but less consistently in humans. The newly recognized presence of brown fat in humans is interesting, and it could clearly contribute to increased metabolic rate, fat oxidation, and thereby insulin sensitivity.
However, its quantitative importance is likely to be limited in view of the relatively small and inconsistent amounts in humans. Perivascular and pericardial fat clearly have a relationship, which may or may not be causative, to atheromatous disease, but a contribution to insulin resistance is uncertain.
Adipose tissue may also influence insulin sensitivity by its secretions, adipokines from adipocytes themselves, or cytokines from adipocytes and infiltrating immune cells whose number increases with adiposity. There is certainly an association between elevated TNFα, CRP, and other inflammatory cytokines with insulin resistance, and in rodents, evidence for an important pathogenic contribution.
However, data from human studies do not support a major role at this stage, although an alternative pathway to NFkB stimulation and impaired insulin signaling could be activated by fatty acids, in conjunction with the hepatokine Fetuin A, through the TLRs.
On the other hand, leptin and adiponectin are clearly important players that should act to ameliorate obesity and insulin resistance but fail to do so—adiponectin because its secretion is paradoxically reduced in obesity, and leptin because of the phenomenon of leptin resistance.
Further understanding of the particular contributions and mechanisms of different fat depots to the metabolic derangements of obesity may help develop improved approaches to limit the epidemic of obesity or at least lessen its adverse metabolic consequences. We thank Miss Suzanne Emery for administrative assistance with this manuscript and Dr.
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Donahue RP , Prineas RJ , DeCarlo Donahue R , Bean JA , Skyler JS. Nuutila P , Knuuti MJ , Maki M , et al. Early cellular markers of insulin resistance in adipose tissue are reduced adipose cell GLUT 4 and IRS 1 protein expression [ 3 — 6 ]. Interestingly, this is seen around four times more frequently in individuals with a genetic predisposition for type 2 diabetes than in subjects lacking a genetic predisposition [ 5 ].
The reason for this is currently unclear but the phenomenon suggests an association between genetic predisposition for type 2 diabetes and a dysregulated adipose tissue. We have recently shown that the ability to differentiate preadipocytes into adipocytes is reduced in cells from adipose tissue characterized by enlarged fat cells [ 7 ].
This seems to predominantly be due to impaired preadipocyte differentiation rather than a lack of early precursor cells including mesenchymal stem cells [ 7 ].
These results clearly indicate that adipose tissue dysfunction is related to adipose cell enlargement. Experiments in animal models also support this concept since, for instance, overexpressing adiponectin in adipose tissue leads to a marked hypercellular obesity without adipose cell enlargement and the animals are at least as insulin sensitive as the lean wildtype mice [ 8 ].
In addition, over expression of GLUT4 in adipocytes leads to hyperplastic obesity and enhanced glucose tolerance [ 9 ]. The increased GLUT4 in fat even overcomes insulin resistance in muscle resulting from genetic deletion of GLUT4 in muscle [ 10 ].
Clearly, adipose tissue function is important for whole body glucose homeostasis. In this study we examined if adipose tissue dysfunction is more closely related to adipocyte hypertrophy rather than to BMI in man.
We investigated GLUT4 expression in adipose cells as a marker of adipose tissue dysregulation in relation to whole-body insulin sensitivity, serum levels of adiponectin and RBP4, as well as the relationship to adipose cell size in a population of non-obese subjects.
All subjects included in the study were healthy non-diabetic offspring of parents with type 2 diabetes. Clinical and biochemical characteristics of the study population are shown in Table 1. The study was approved by the ethical committee of the University of Gothenburg and performed in accordance with the Declaration of Helsinki.
Written consent was obtained from each subject. Height and weight were measured to the nearest cm and 0. Circulating plasma glucose was determined using a photometric method by the accredited central hospital laboratory and insulin concentrations by a micro-particle enzyme immunoassay Abbott Laboratories, Tokyo, Japan.
The mean amount of glucose infused during the last hour was used to calculate the rate of whole-body glucose uptake. Non-esterified fatty acids in serum were measured by an enzymatic colorimetric method Wako Chemicals, Neuss, Germany while other plasma lipid concentrations were determined with an automated Cobra Mira analyser Hoffman-LaRoche, Basel, Switzerland.
Circulating adiponectin levels were measured in serum by a human adiponectin ELISA-kit B-Bridge International, Sunnyvale, CA, USA according to the manufacturers instructions and serum RBP4 by quantitative Western Blot [ 11 ].
Human abdominal subcutaneous adipose tissue was obtained in the fasting state by needle biopsy. Isolation of adipocytes was performed essentially as previously described [ 7 ]. Adipocyte cells were placed on a siliconized glass slide and consecutive cell diameters were measured with a calibrated ocular.
Isolated human adipocytes were separated from medium by centrifugation through dinonyl phthalate. Protein concentration was measured using the bicinchonic acid method Pierce, Rockford, IL, USA. Protein were separated on SDS-PAGE as described [ 4 ] and immunoblotted with an anti-GLUT4 antibody Chemicon, Temecula, CA, USA.
Total cellular RNA was extracted from abdominal subcutaneous adipose tissue biopsies with the guanidinium thiocyanate method as described [ 13 ].
Gene expression was analyzed with the ABI PRISM HT sequence detection system TaqMan, Applied biosystems, Foster City, CA, USA. All data are presented as mean ± SD. Data was tested for normality and, if appropriate, Log transformed. Linear correlations and adjustment for gender and exercise were performed using PASWstatistics SPSS Inc.
P-values were adjusted for multiple testing using the Bonferroni-Holm correction algorithm SAS. We characterized adipose tissue GLUT 4 protein and gene expression in 32 individuals with BMI range These individuals were part of a large inter-European study, EUGENE2, relating phenotype to genotype.
The inclusion criteria and phenotyping procedures have been reported previously [ 14 ]. The clinical characteristics of the cohort studied here are shown in Table 1. Furthermore, insulin sensitivity correlated with, s-HDL-cholesterol, total s-adiponectin levels, and adipose tissue GLUT 4 protein expression and mRNA levels, and inversely with s-triglycerides and s-RBP4 Table 2.
Adjusting for exercise alone did not affect the results. These results support the concept that insulin sensitivity is more closely related to adipose cell size and adipose tissue distribution than to BMI. Adipose cell size also correlated with other known metabolic consequences of insulin resistance including circulating insulin levels and total triglyceride levels Table 2 and Figure 1 a.
Adipocyte cell size correlations. BMI also tended to correlate with circulating adiponectin levels. The correlation was, however, not as strong as with adipocyte cell size Figure 1 b. Furthermore, adipose cell size was inversely correlated to adipose tissue GLUT4 gene expression and a trend for this was also found at protein level Figure 1 c.
In addition, a borderline significant negative correlation was found with circulating RBP4 levels Table 2 while no association could be found between circulating RBP4 and BMI.
Adjusting for exercise did not change the results. We then examined GLUT4 expression in the adipose tissue in relation to insulin sensitivity and circulating adiponectin and RBP4 levels. Circulating adiponectin levels tended to correlate positively with GLUT4 gene and protein expression.
Adiponectin correlated negatively with serum RBP4 levels Figure 2 , which was not affected by exercise. Adiponectin levels also correlated positively with degree of insulin sensitivity Table 2 , HDL-cholesterol and negatively with fasting insulin and HbA1c levels Table 3.
Thus, both markers of insulin sensitivity; i. Circulating factors. Adipose tissue inflammation is increased in hypertrophic obesity and promotes dysregulated adipose tissue biology [ 17 ].
In line with these findings, we have previously shown that the inflammatory cytokine IL-6 is elevated in hypertropic obesity and that the interstitial concentration correlates with cell size [ 18 ]. Another possible candidate for adipose tissue dysregulation associated with hypertrophic obesity is HIF-1alpha since cellular hypoxia has been demonstrated to occur when the adipose cells expands [ 19 ].
However, we found no correlation between either adipose cell size, insulin sensitivity or any of the markers of insulin resistance with HIF-1alpha mRNA levels or the HIF-1alpha-induced gene VEGF in these non obese subjects Table 4.
The results from these analyses may have been affected by the reduced number of subjects included due to limited mRNA or tissue availability. A number of studies have established that adipose tissue dysfunction contributes to metabolic dysfunction and type 2 diabetes.
Enlargement of adipocyte cell size has been shown to be associated with adipose tissue dysfunction and, in addition, to predict later development of type 2 diabetes in Pima Indians, a population with high propensity for obesity and type 2 diabetes [ 20 ], as well as in a Swedish cohort of middle-aged women [ 21 ].
Although obesity is a major risk factor for the development of type 2 diabetes, not all obese individuals become insulin resistant or develop type 2 diabetes.
Recently, it was shown by Klöting et al. This finding was also associated with reduced tissue inflammation and higher insulin-stimulated glucose uptake at least in omental adipose tissue.
Furthermore, by comparing non-obese subjects with a known genetic predisposition for either type 2 diabetes or obesity, we have recently shown that for a given amount of body fat individuals with a genetic predisposition for type 2 diabetes had an inappropriate enlargement of their abdominal adipocyte cell size.
This difference was evident when they were compared to subjects with a genetic predisposition for obesity or to control subjects lacking a known genetic predisposition [ 23 ]. Clearly, adipocyte cell size and function are related to whole body insulin sensitivity. com [ 14 ]. This program focused on carefully phenotyping individuals at risk for type 2 diabetes by virtue of having at least one first degree relative with this condition.
This cohort has undergone several genotyping studies and is followed prospectively in order to identify future diabetes development. The individuals included in this study were healthy and non-obese, but they are a high-risk group even though current obesity was not part of the risk profile.
Furthermore, they are more insulin-resistant, as a group, than matched control subjects without a family history of type 2 diabetes [ 5 ]. The results from the present study show that markers of adipose tissue dysregulation are present already in these otherwise healthy individuals. Adipose cell size, GLUT 4 protein and mRNA expression as well as circulating levels of adiponectin and RBP4 were all markers for degree of insulin sensitivity.
Interestingly, adipose cell size was positively correlated with serum RBP4, which is consistent with previous findings [ 24 ], and inversely with adiponectin levels as well as with GLUT 4 expression.
These findings are consistent with the concept that adipose cell expansion, even over the limited range of BMI in this cohort, is associated with insulin resistance as well as markers of a dysregulated adipose tissue measured as low GLUT4 expression and circulating levels of adiponectin and high serum RBP4 levels.
It should also be pointed out that we did not measure APM1 mRNA levels since this molecule is subject to important post-transcriptional modifications as well as a regulated secretion pathway [ 25 ], thus making mRNA levels less dependent than total protein secreted and present in the blood.
Virtually all clinical studies on the role of adiponectin have also focused on the circulating levels of this protein. It is also noteworthy that while circulating adiponectin levels were only border-line correlated to BMI and serum RBP4 levels not at all, the association with adipose cell size was highly significant.
These findings are in line with the results presented by Klöting et al. where circulating adiponectin is decreased and RBP4 increased in equally obese individuals with enlarged adipocytes and reduced insulin sensitivity [ 26 ].
The lack of correlation with BMI is probably due to the relatively limited range of BMI in this cohort since BMI is well known to be associated with insulin sensitivity in large population samples with different degree of obesity. Thus, this study shows that adipose cell size and adipose tissue distribution are more sensitive parameters over a relatively limited range of BMI in a cohort of non-obese subjects.
In addition, these results show that adipose tissue dysregulation does not require obesity per se but rather hypertrophic adipose cells. This is in line with recent findings showing that the number of new adipocytes generated each year is reduced in subjects with adipocyte hypertrophy while the relative death rate is unchanged [ 27 ].
What constitutes the blockage is still unknown, but clearly the resulting adipocyte hypertrophy is associated with adipose tissue dysfunction.
We here show that this is also related to reduced insulin sensitivity combined with a metabolic risk profile and markers of adipose tissue dysregulation. It is well known that adipose tissue distribution differs between men and women but, interestingly, it has also been shown that the proportion of early-differentiated adipocytes, measured as percentage of PPARgamma expressing cells in the subcutaneous adipose tissue is increased in women when compared to men indicating that there may be important gender-related differences in pre-adipocyte recruitment, proliferation and differentiation potential [ 28 ].
Our results show that the correlation between adipocyte cell size and GLUT4 as well as the insulin resistance marker RBP4 are affected by gender. This is also true for the association between adiponectin and GLUT4, both markers of late adipocyte differentiation and function. These findings add further strength to the concept of gender differences in adipocyte differentiation and function.
Tchoukalova et al. Sex steroid-hormones have been shown to influence fat distribution [ 29 ] as well as adipocyte differentiation [ 30 ] and could well be responsible for the gender differences observed. Unfortunately, we did not measure sex-steroids in the present study.
However, a recent paper investigating clinical characteristics associated with insulin sensitivity in women with polycystic ovary syndrome PCOS showed that the strongest predictors of insulin sensitivity in this group were adipocyte cell size, adiponectin and WHR, while sex steroid-hormones were excluded from the regression model [ 31 ].
Further studies are required to elucidate the importance of, and mechanisms behind, these gender-associated differences. It is well established that enlarged adipose cells leads to infiltration of macrophages and other inflammatory cells, including mast cells [ 32 — 34 ].
The presence of inflammatory cells in the adipose tissue affects the micro-environment and can impair adipocyte differentiation [ 7 , 17 ].
Indeed, macrophage infiltration in the omental adipose tissue depot, together with circulating adiponectin was found to almost completely explain the degree of insulin sensitivity in severely obese individuals [ 26 ]. We previously measured the inflammatory cytokine IL6 in adipose tissue and showed that expression, secretion and, as a consequence, also interstitial levels of this cytokine were increased in the adipose tissue characterized by enlarged fat cells [ 18 ].
Thus, inflammation seems to follow adipose cell size enlargement and this is also associated with impaired adipocyte differentiation [ 35 ]. Cellular hypoxia has also been implicated in adipose tissue dysregulation in obesity [ 19 ].
However, we found no relationship between HIF-1alpha mRNA levels, or VEGF , which is an HIF-1alpha-regulated gene [ 36 ], and adipose cell size or any marker of insulin resistance. This is in agreement with previously reports in obese individuals where the expression in subcutaneous adipose tissue was unrelated to the degree of insulin sensitivity or cell size.
In contrast, the expression of HIF-1alpha has been shown to be up-regulated in insulin resistant omental adipose tissue in severe obese individuals [ 26 ]. Thus, although HIF-1alpha may play a role in severe obesity, we did not find any association between insulin sensitivity and HIF-1alpha in this small group of individuals with hypertrophic adipocytes.
The results of the present study clearly show that enlarged abdominal adipose cells are associated with reduced systemic insulin sensitivity irrespective of whether obesity is present or not. A likely reason for the insulin resistance is altered RBP4 and adiponectin levels as well as an inability to store additional lipids in the subcutaneous depot during weight gain.
This leads to storage in ectopic sites including visceral depots, liver and muscle which, in turn, further promotes insulin resistance Reviewed in [ 15 , 37 ]. Elegant experiments in mouse models have indeed shown that mice overexpressing adiponectin in the subcutaneous adipose tissue become grossly obese with hypercellular adiposity as a consequence of new preadipocyte recruitment and differentiation.
The changes associated with this transgene did not impair insulin sensitivity at all [ 8 ]. The present results further support the concept that pre-adipocyte recruitment and hypercellular obesity can prevent the development of insulin resistance.
The present study is limited by its small number of subjects and using the quite conservative methods available to correct for multiple testing leaves few significant correlations. However, regardless of these limitations, the results provide important information in a high-risk cohort of first-degree relatives to type 2 diabetic patients showing that a dysregulated adipose tissue occurs early and is associated with insulin resistance.
Future studies, such as long-term follow-up studies of the EUGENE 2 cohorts may provide further evidence for this concept as a risk to develop type 2 diabetes as well.
The findings in the present paper support the concept that it is not obesity per se, but rather metabolic dysfunction in the adipose tissue that is associated with systemic insulin resistance and the metabolic syndrome. Future prospective studies may provide final evidence of this concept and the relative importance of its different components.
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Int J Obes Relat Metab Disord. Carvalho E, Jansson PA, Axelsen M, Eriksson JW, Huang X, Groop L, Rondinone C, Sjostrom L, Smith U: Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. FASEB J. CAS PubMed Google Scholar. Carvalho E, Jansson PA, Nagaev I, Wenthzel AM, Smith U: Insulin resistance with low cellular IRS-1 expression is also associated with low GLUT4 expression and impaired insulin-stimulated glucose transport.
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Article PubMed Central CAS PubMed Google Scholar. Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, Schraw T, Durand JL, Li H, Li G, et al: Obesity-associated improvements in metabolic profile through expansion of adipose tissue.
Obesity-associated sensitigity resistance is adipositu major Insulin sensitivity and adiposity factor for type 2 Citrus aurantium oil and cardiovascular disease. In the past decade, Insulin sensitivity and adiposity zdiposity number of endocrine, inflammatory, neural, and cell-intrinsic adiposityy have been shown to Isulin dysregulated in obesity. Sensitivitty it is adiposihy Insulin sensitivity and adiposity one of these factors plays a dominant role, many of these factors are interdependent, and it is likely that their dynamic interplay underlies the pathophysiology of insulin resistance. Understanding the biology of these systems will inform the search for interventions that specifically prevent or treat insulin resistance and its associated pathologies. The number of obese individuals worldwide has reached 2. Obese individuals develop resistance to the cellular actions of insulin, characterized by an impaired ability of insulin to inhibit glucose output from the liver and to promote glucose uptake in fat and muscle Saltiel and Kahn ; Hribal et al.Insulin sensitivity and adiposity -
Of note, not every brain responds equally to insulin. A substantial number of people display an attenuated or absent insulin response, an observation often referred to as brain insulin resistance 6. A number of factors that associate with brain insulin resistance have been identified so far.
These range from alterations at the blood brain barrier to genetics 6. Among them, obesity is the best studied in animals and humans 1 , 8. Although, for most of these factors, including obesity, it is still unclear whether they are cause or consequence of brain insulin resistance.
Besides controlling higher brain functions, insulin also influences outflows that modulate peripheral energy metabolism 6. Based on research in animals 9 , experimental studies in humans suggested that brain insulin affects peripheral lipid metabolism in visceral adipose tissue 10 and liver More importantly, insulin delivery to the brain improves whole-body insulin sensitivity 12 , 13 , 14 by suppressing endogenous glucose production 14 , 15 and stimulating glucose uptake into peripheral tissues Research in animals and humans identified the hypothalamus as one crucial region for this process 13 , 14 , As brain insulin resistance also impairs the central nervous control over peripheral energy metabolism, it has been hypothesized that this impairment could result in altered substrate distribution with preferential energy accumulation in unfavorable fat depots 14 , Whether body fat accumulation has detrimental effects on cardiometabolic health is mainly determined by its location This observation has led to the concept of metabolic healthy obesity with energy storage mainly in the subcutaneous compartment versus unhealthy obesity, with fat accumulation mainly in the visceral space To test whether brain insulin sensitivity affects the long-term weight course and contributes to the development of healthy versus unhealthy body fat distribution, we analyzed two datasets with whole-body MR imaging available.
The first comprises long-term follow-up data of 15 participants in whom brain insulin sensitivity was determined by magnetoencephalography before they entered a lifestyle intervention program. The second is a cross-sectional cohort of participants with precise functional MR imaging of hypothalamic insulin action.
So far, brain insulin resistance was identified to be associated with less weight reduction during the first 9 months of lifestyle intervention in our TULIP study We started our current analyses by testing the impact of brain insulin sensitivity on body weight and body fat distribution in the years following the month lifestyle intervention Supplementary Table 3.
Participants with high brain insulin sensitivity before entering the lifestyle intervention program achieved a greater reduction in body weight and total adipose tissue Fig. By contrast, brain insulin-resistant individuals showed a slight weight loss in the first 9 months of the program, and already regained body weight as well as total and visceral adipose tissue during the subsequent months of lifestyle intervention Fig.
a Changes in body weight; b changes in visceral adipose tissue VAT ; c changes in subcutaneous adipose tissue SCAT. Brain insulin sensitivity was assessed as change in the theta frequency band in response to insulin infusion, corrected for saline infusion by magnetoencephalography.
Filled boxes represent participants with brain insulin responsiveness below the median, open circles represent participants with brain responsiveness above the median.
Continuous variables were used for statistical analyses and stratified variables were used solely for better illustration of the results. Source data are provided as a Source Data file.
In the long-term follow-up, 9 years after the lifestyle intervention, baseline brain insulin sensitivity was associated with less regain in body weight Fig. In addition, baseline brain insulin sensitivity was associated with a smaller increase in total adipose tissue and visceral fat content at long-term follow-up Fig.
As insulin action in the hypothalamus is crucial for the brain-derived modulation of peripheral energy metabolism, we tested whether insulin responsiveness in this brain area associates with body fat distribution. After food intake, regional cerebral blood flow in the hypothalamus is physiologically reduced Accordingly, reduction of blood flow after intranasal insulin application indicates high brain insulin sensitivity persons with high insulin sensitivity of the hypothalamus had less visceral adipose tissue.
Region-specific change in cerebral blood flow in response to intranasal insulin administration was extracted for the hypothalamus as region of interest a.
Participants with a strong insulin-induced suppression in hypothalamic blood flow had significantly less visceral adipose tissue b. Subcutaneous fat content was not associated with insulin sensitivity of the hypothalamus c.
The ratio of visceral to subcutaneous adipose tissue was favorably lower in those with strong insulin-induced hypothalamic blood flow d. Lines represent fit lines ±CI. p values are from unadjusted linear regression models.
Furthermore, hypothalamic insulin response was associated with glucose metabolism. Our current results indicate that brain insulin action contributes to long-term weight course as well as to the distribution of fat throughout the body.
Participants with high brain insulin sensitivity before lifestyle intervention lost more body weight and body fat during the 24 months of the program. In addition, brain insulin sensitivity assessed before lifestyle intervention was associated with a lower regain in body weight and body fat in the long-term follow-up.
We already reported an association between high brain insulin sensitivity and immediate loss of body weight and body fat during the first 9 months of our program We now established that this relation persists throughout the entire 24 months of lifestyle intervention.
Even more importantly, low brain insulin sensitivity was linked to a regain in body weight and body fat in the 9 years following the program. This association was present for the amount of visceral fat and the visceral fat content adjusted for the total amount of adipose tissue.
Of note, no such association was detected for subcutaneous fat in our longitudinal data. In line with earlier data in a smaller cohort 22 , our current cross-sectional analyses confirmed an association between hypothalamic insulin sensitivity and visceral fat content, but not with subcutaneous adipose tissue.
Brain insulin action impacts several brain circuitries that are crucial to eating behavior. Insulin in the human brain affects the response to food cues and, ultimately, food intake 5 , 23 , mechanisms that most likely contribute to our current findings on the dietary response during lifestyle intervention and on the long-term weight regulation.
However, the regulation of food choice and food intake does not appear to be the only underlying mechanisms, particularly for the association with body fat distribution. It is worth mentioning that brain insulin action modulates postprandial systemic insulin sensitivity and postprandial energy fluxes in peripheral metabolic organs via the autonomic nervous system 8 , 13 , 14 , 24 , In this context, the administration of insulin to the human brain boosts the suppression of endogenous glucose production and promotes the uptake of glucose into the peripheral organs Both these mechanisms can orchestrate postprandial energy fluxes, and help to prevent excessive energy storage in the visceral fat compartment 17 and can therefore contribute to our current findings.
This fat depot specific effects of brain insulin action could further be determined by differential autonomic innervation of subcutaneous and visceral fat 26 , Both fat depots are innervated by distinct sympathetic and parasympathetic motor neurons with functional consequences of autonomic balance on adipocyte insulin sensitivity and energy storage The proximal regulatory neurons that project into the adipose tissue appear to reside in the hypothalamus 27 , Thus, changes in autonomic nervous system balance that are induced by brain insulin action 8 , 13 , 14 , 24 , 25 could exert differentially effects on subcutaneous and visceral adipocytes and thereby contribute to our current findings.
In line with this hypothesis, induction of brain insulin action was found to modulate systemic but not subcutaneous lipolysis in humans Our current findings are of particular importance, given that the enlarged visceral fat content not only poses a high risk factor for the subsequent development of diabetes, but is also robustly linked to the risk of cardiovascular disease and the development of cancer Brain insulin resistance therefore seems to be involved in the pathogenesis of obesity in general.
More importantly, it appears to be a determinant of healthy and unhealthy obesity. Unfortunately, only a limited sample size was available in our longitudinal cohort.
MEG and fMRI most likely capture different aspects of brain insulin sensitivity and their comparability in this regard has not been tested so far. In conclusion, we showed that high brain insulin sensitivity was linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution.
Our current results underline the importance of brain insulin action for the development of body weight and body fat distribution. As visceral fat is strongly linked to diabetes, cardiovascular risk, and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve insulin resistance of the human brain.
Details on the TULIP lifestyle intervention study, including primary and secondary outcomes as well as inclusion and exclusion criteria, have been reported previously The study was conducted within the Deutsche Forschungsgemeinschaft DFG project KFO Three hundred participants at high risk for type 2 diabetes completed the intervention.
As reported in ref. In a subgroup of 28 participants, brain insulin sensitivity was assessed by MEG before lifestyle intervention. Of these, 15 individuals were followed-up after 9. Total dietary energy intake was assessed in 10 of these participants at three time periods during the lifestyle intervention before, during the first 9 months of lifestyle intervention, and during month 9—24 of lifestyle intervention by the mean values of several 3-day food diaries obtained at each visit In all participants, body fat distribution was assessed by whole-body MRI as part of the baseline examination of clinical trials clinicaltrials.
gov: NCT, NCT, NCT, NCT, NCT, NCT For patients characteristics, see Supplementary Table 2. Whole-body MRI was performed in the early morning after overnight fasting on a 1. Detailed information is given in ref. Before lifestyle intervention, participants underwent two hyperinsulinaemic—euglycaemic glucose clamps with insulin or placebo saline infusion on two different days for details see Tschritter et al.
Cerebrocortical activity was assessed by magnetoencephalography MEG before and during the clamp experiment. The power spectrum for the spontaneous activity of the participants was analyzed by a standard statistical mapping procedure taking into account multiple comparison correction for the different frequency bands.
On the basis of earlier findings 20 , assessment of the cerebrocortical insulin effect as changes in theta activity during the insulin experiment corrected for the placebo experiment were calculated Participants underwent whole-brain fMRI at a 3.
Experiments were conducted after an overnight fast and started under basal condition to quantify cerebral blood flow CBF with a pulsed arterial spin labeling PASL measurement using a PICORE-Q2TIPS sequence proximal inversion with control for off-resonance effects—quantitative imaging of perfusion using a single subtraction.
Change in CBF was extracted from the hypothalamus based on recent findings All relevant ethical regulations were complied with and informed written consent was obtained from all participants. The local ethics committee approved the study protocols Ethics Committee of the Medical Faculty of the Eberhard-Karls-Universität and the University Hopsital Tübingen.
In the longitudinal study, changes in body weight, body fat depots, and further metabolic variables and their association with baseline brain insulin sensitivity theta activity were analyzed by MANOVA.
Continuous variables were used for analyses and stratified variables were used solely for better illustration of the results. For the cross-sectional study, correlations between body fat compartments and hypothalamic cerebral blood flow fMRI measurements were analyzed by linear regression models unadjusted and adjusted for sex and age as well as BMI.
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
The data that support the findings of this study are available on reasonable request from the corresponding author M. The source data underlying Figs. Kullmann, S. et al. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans.
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Permissions Icon Permissions. Abstract Context and Objective:. Figure 1. Open in new tab Download slide. Table 1. Subject Characteristics. Variable a. Other studies also suggest that metabolic improvement, induced by salsalate treatment, is mediated through AMPK activation Hawley et al.
Although the effects on glycemic control are modest, the salsalate is not expensive and has a very safety profile. In , a preclinical study clearly showed the role of TNF-α in the pathophysiology of IR in the AT Hotamisligil et al. However, the results of clinical studies have so far been disappointing.
For instance, TNF-α neutralizing antibodies have been shown to be effective for the treatment of many other inflammatory diseases, and some patients have shown slight improvements in glycemic control Ofei et al.
However, prospective studies in T2D patients have been confusing. In spite of valuable effects in mice, a human clinical trial showed that anti-TNF-α therapy leads to no improvements in insulin sensitivity in patients with T2D Ofei et al.
In contrast, a study performed in obese subjects without T2D showed that an inhibition of TNF-α for 6 months is able to reduce fasting glucose and increase adiponectin levels Stanley et al. IL-1β is a strong mediator of the obesity-induced inflammation and participates in the pathogenesis of T2D, mediating the adverse consequences of hyperglycemia on pancreatic β-cells Maedler et al.
Antagonism of IL-1R for 13 weeks, in a proof-of-concept study of patients with T2D, shows an improved glycemic control and secretory function of the pancreatic β-cells and the reduced markers of systemic inflammation Larsen et al. The follow-up study on the same population proves that 39 weeks after the last IL-1R antagonist administration, β-cell insulin secretion is still increased and CRP decreased Larsen et al.
The long-term effects are probably due to the block of IL-1β auto induction mechanism Böni-Schnetzler et al. Further studies have also noted that the use of antibodies directed against IL-1β has potential benefits in the treatment of T2D, as it significantly reduces HbA1c levels Cavelti-Weder et al.
Recently, a multicenter randomized controlled trial, specifically designed to evaluate the glycemic outcome, enrolled participants, with RA and T2D followed up for 6 months. Thirty-nine participants were randomized to IL-1R antagonist anakinra or TNF inhibitors TNFi to assess the efficacy of these drugs in controlling glucose alterations of T2D Ruscitti et al.
Regarding RA, there has been a gradual reduction in disease activity in both groups. In conclusion, results of this research indicate a specific effect of IL-1 inhibition in subjects with RA and T2D, reaching the therapeutic targets of both disorders and improving the main outcome of enrolled participants.
A clearer reduction of HbA1c, comparing this to the previous study on T2D Larsen et al. On this basis, IL-1 pathway can be considered a shared pathogenic mechanism, and a single treatment that manages both diseases appears to be a promising option for improving the care of RA and T2D patients Giacomelli et al.
Thiazolidinediones TZDs are antidiabetic drugs that improve insulin sensitivity and glycemia, as they function as agonists for PPARγ nuclear receptor Yki-Järvinen, TZDs have also anti-inflammatory effects; they repress NF-κB action and reduce the expression of its target genes Pascual et al.
The inhibition of NF-κB pathway reduces ATM content Esterson et al. Furthermore, the ability of TZDs to reduce circulating inflammatory mediators such as CRP and MCP-1 seems to be independent of glycemic control Pfützner et al.
Therefore, TZDs act through different mechanisms and the anti-inflammatory properties of these drugs are not definitely established. The mechanism of metformin action is not completely explained, but it decreases glycemia by reducing hepatic glucose production and raising glucose uptake in peripheral tissues Inzucchi et al.
In addition to its clear metabolic effects, metformin has also anti-inflammatory properties; for instance, it directly inhibits the production of reactive oxygen species in the mitochondria and can reduce the production of many cytokines Wheaton et al. Emerging evidence supports the novel hypothesis that metformin can exhibit immune-modulatory features.
Decreased ATP concentration causes AMPK activation, and among several targets, AMPK inhibits the mammalian target of rapamycin mTOR Zhou et al. mTOR is crucial for cellular metabolism, cytokine responses, antigen presentation, macrophage polarization, and cell migration Weichhart et al. Metformin can also regulate other pathways relevant to immune cells, including NF-kB Hattori et al.
Indeed, other studies have proved that metformin is able to inhibit TNF-α-induced activation of the NF-κB axis and IL-6 production Huang et al. Metformin, in a dose-dependent manner, reduces IL-1β production in lipopolysaccharide-activated macrophages, and the effect is independent of AMPK activation Kelly et al.
Moreover, metformin concurrently decreases circulating inflammatory proteins, including CRP, in impaired glucose tolerance and T2D patients De Jager et al. The anti-inflammatory effects of metformin, like TZDs, appear to be independent of glycemic control Caballero et al.
In murine models, the attenuation of the inflammatory state has been shown to be effective in improving the obesity-induced IR; however, there are ongoing clinical trials in humans to confirm the therapeutic potential of metformin. This issue represents an essential step in proving the translational relevance of these observations.
T2D is a heterogeneous disorder, and the absence of clinical biomarkers, showing whether the treatments have anti-inflammatory effects in the AT, is a potential issue complicating the analysis Donath, The identification and profiling of these biomarkers in T2D patients would allow us to predict those that should respond to an anti-inflammatory therapy.
The global obesity epidemic results in a higher incidence of metabolic disorders. The mechanisms underlying the association between obesity and IR have not yet been fully explained. Therefore, further well-designed clinical and basic research studies are needed to establish this relationship.
From our point of view, inflammation occurring in the AT during obesity is the primary mechanism for developing local and systemic IR. AT is the primary whole-body regulator of lipid and glucose homeostasis and is no longer considered merely a storage tissue.
Obesity leads to severe adipocyte disorders by altering the amount and activity of almost all resident immune cells. The imbalance of immunological phenotypes is correlated with the development of persistent local inflammation during which several biologically active molecules are released.
These molecules affect distal tissues and organs, such as skeletal muscle and liver. The inflammatory nature of obesity opens new prospects in the development of therapeutic strategies for the treatment of its related metabolic complications.
However, there are still a lot of issues that need to be addressed. Anti-inflammatory strategies have proven to be effective in improving obesity-induced IR in murine models.
However, clinical studies are still ongoing to confirm the therapeutic potential in obese and insulin-resistant individuals. Another issue is the modest effects of anti-inflammatory therapies observed in these studies.
Targeting only one inflammatory molecule may not be sufficient to have a beneficial effect; therefore, we could hypothesize the combined use of more anti-inflammatory therapies. In addition, a recent study showed that acute and transient inflammation is essential for healthy AT expansion and remodeling in obesity Asterholm et al.
This finding raises further questions on the effectiveness of anti-inflammatory therapies in the treatment of obesity-induced metabolic disorders. Inflammation is a finely regulated mechanism, and all defects in its balance can cause AT dysfunction. In the era of personalized and precision medicine, increasing our knowledge of the obesity-induced inflammation mechanisms might enable us to overcome the limitations of the traditional anthropometric indices of obesity.
These anthropometric indices are not correlated with obesity-induced metabolic complications and additional clinical parameters need to be identified for risk assessment Longo et al.
From our point of view, given the strong association between inflammation and obesity complications, circulating inflammatory biomarkers may be used for the risk assessment of these diseases in the future.
The identification and evaluation of these biomarkers in obese patients will allow the prediction of those who will develop obesity-associated metabolic complications. FB and CM conceived the idea and edited the manuscript.
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Han-Chow E. Koh adiposjty, Stephan znd VlietTerri A. PietkaGretchen A. MeyerBabak AmdRichard XdipositySesnitivity J. GroplerDetoxify your liver Insulin sensitivity and adiposity Subcutaneous Adipose Tissue Adipozity Function Insylin Insulin Sensitivity in People With Obesity. Diabetes 1 October ; 70 10 : — We used stable isotope—labeled glucose and palmitate tracer infusions, a hyperinsulinemic-euglycemic clamp, positron emission tomography of muscles and adipose tissue after [ 18 F]fluorodeoxyglucose and [ 15 O]water injections, and subcutaneous adipose tissue SAT biopsy to test the hypotheses that 1 increased glucose uptake in SAT is responsible for high insulin-stimulated whole-body glucose uptake in people with obesity who are insulin sensitive and 2 putative SAT factors thought to cause insulin resistance are present in people with obesity who are insulin resistant but not in those who are insulin sensitive.
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