Visceral fat and insulin resistance -
Therefore, low adiponectin concentrations contribute to impaired glucose homeostasis and insulin resistance [ 35 ]. Insulin resistance manifests itself differentially in various tissues, which contributes to the overall phenotype of VAS.
For example, insulin resistance in: 1 WAT, results in lipolysis, increasing free fatty acids into the circulation, which exacerbate the deleterious cycle of hyperlipidemia—inflammation—insulin resistance; 2 the liver, results in increased hepatic glucose production via glycogenolysis and gluconeogenesis , contributing to hyperglycemia [ 32 ].
Insulin resistance in some of the former target sites aggravates glycemic homeostasis, increasing the formation of advanced glycation end products AGEs.
AGEs are derived from non-enzymatic reactions between glucose and proteins, nucleic acid and lipids. Endogenously derived AGEs, as well as exogenously generated AGEs formed during high-heat cooking, can promote inflammation.
This happens via receptors that bind to advanced glycation end products, such as RAGE advanced glycosylation end product-specific receptor , TLR4 and other receptors that regulate the activity of NFκB [ 47 ], constituting another link between diet and insulin resistance.
An interesting aspect that deserves attention concerns the effects of compensatory hyperinsulinemia: although it is usually considered a by-product of the insulin resistance, hyperinsulinemia exerts its effects, overstimulating certain pathways of insulin action in various cells [ 27 ]. For instance, the expression of Sterol Regulatory Element Binding Protein 1c SREBP1c , a transcription factor that modulates the expression of lipogenic enzymes, is increased by chronic hyperinsulinemia in the liver of mice exhibiting insulin resistance.
As a result, de novo fatty acid biosynthesis is enhanced and contributes to non-alcoholic fatty liver disease NAFLD [ 48 ], the hepatic component of the VAS. Another potential consequence of prolonged hyperinsulinemia is the exacerbation of inflammation since it has been demonstrated that in vitro, insulin exerts long-term proinflammatory action, by amplifying effects of the cytokine-NFkB axis [ 49 ].
If so, then hyperinsulinemia could be one of the mechanisms proposed to explain the increased frequency of cancer that accompanies the obesity epidemic [ 50 ]. Other mechanisms that may explain the increased cancer risk include the mitogenic effect of insulin through either insulin-like growth factor-1 IGF1 receptors or through hybrid IGF1-insulin receptors as well as the increased concentrations of free IGF1, as a consequence of the lower concentrations of IGF binding proteins 1 and 2 IGFBP1 and IGFBP2 in obese individuals [ 51 ].
During embryonic development, there is significant plasticity, which attempts to adjust the foetal gene expression to the environment, so that the resulting phenotype is adapted to the environmental conditions [ 52 ]. Thus, fetuses exposed to suboptimal conditions during intrauterine life for instance, protein-calorie undernutrition undergo alterations in gene expression to adjust.
However, if the post-natal life provides different conditions from those previously anticipated for instance, abundance of nutrients , the body will not be prepared for that environment, and is more likely to develop disease [ 53 ].
This ability to sustain the changes acquired in intrauterine life in the post-natal life relies on epigenetic mechanisms, namely, post-translational modifications within histones, DNA cytosine methylation and control of gene expression by micro-non-coding RNAs.
The Dutch famine has been used to investigate the effects of in utero stress among adults who were born in the western part of The Netherlands at the end of World War II. These individuals were exposed prenatally to undernutrition.
The Dutch Famine Cohort study has shown that individuals exposed to maternal undernutrition at any stage of gestation had increased glycaemia as adults.
Women exposed to undernutrition at early stages of gestation appeared to be more centrally obese than those not prenatally exposed to famine [ 56 ]. Interestingly, higher methylation of genes related to metabolic and cardiovascular diseases, such as the ones encoding leptin, IL10 and ABCA1 were found in individuals prenatally exposed to famine in comparison to their unexposed same-sex siblings [ 57 ].
In the same line of investigation, specific associations of low birth weight with VAS were observed in other populations [ 58 , 59 ], strongly suggesting that, besides environmental and genetic conditions, prenatal reprogramming participates in the susceptibility to the VAS.
Another player recently recognized as important in the development of VAS is the gut microbiota, comprised of approximately trillion microbes resident in the human intestines, the majority of them belonging to the phyla Firmicutes and Bacteroidetes.
The gut microbiota is influenced by diet composition, which, in turn, influences how food is processed in the gastrointestinal tract [ 60 ]. Pathobionts resident microbes with pathogenic potential [ 61 ] increase by diets enriched in saturated fat, damage the intestinal epithelial cell layer and enable the translocation of one key constituent of many bacteria, lipopolysaccharide LPS , from the gut lumen into the systemic circulation [ 62 ].
LPS molecules bind to TLRs, activating the proinflammatory signaling cascades previously mentioned and eliciting insulin resistance; in the liver, for instance, activation of TLR4 and TLR9 augments TNFα secretion and participates in NAFLD development [ 60 ].
On the other hand, a fiber-rich diet exerts beneficial effects on the microbiota composition, decreasing the Firmicutes : Bacteriodetes ratio and consequently increasing fiber degradation and the production of short-chain fatty acids, such as acetate, propionate, and butyrate [ 63 ], which are absorbed in the colon.
Acetate and propionate are substrates for lipogenesis and gluconeogenesis while butyrate provides energy for colonic epithelial cells [ 60 ]. Additionally, these compounds bind to widely expressed G-protein coupled receptors GPR41 and GPR43 , augmenting energy expenditure, insulin sensitivity, satiety and production of glucagon-like peptide 1 GLP1 and decreasing inflammation, thereby protecting against VAS [ 62 ].
The CNS is an important modulator of food intake through different hormonal and neuropeptide signaling pathways [ 64 ]. Neuropeptides regulate energy storage in white adipocytes and inhibit brown adipose tissue activation in mammals [ 65 ].
Experimental and clinical studies showed a relation between the autonomic nervous system, dietary intake and adipose tissue. Body fat distribution of body fat is a more important risk factor for the development of hypertension and cardiovascular disease than obesity generally.
Sympathetic nervous system SNS activity contributes to obesity-induced hypertension [ 66 ]. Independently of body fat distribution, sympathetic activity seems to be related to different components of the VAS.
By stratifying patients with similar obesity degrees according to the presence or absence of high blood pressure, we found a higher surrogate markers of sympathetic activity derived from spectral analysis and greater impairment in several components of Metabolic syndrome in those subjects with high blood pressure [ 67 ].
It suggest that high blood pressure carriage in pararel with sympathetic activity in this population. Nonetheless, SNS activity was associated to obesity in obese normotensive subjects [ 68 ]. The distribution of body fat seems to be more important to determine the cardiovascular risk than the whole body fat.
Alvarez et al. showed a higher sympathetic activity in men with visceral obesity compared to subcutaneous fat levels [ 69 ]. Leptin, an important product of visceral adipocytes, is related to increased sympathetic activity, with human obesity-induced hypertension, and associated to a increased termogenic metabolism [ 70 ].
The SNS also plays a role in the regulation of mammalian thermogenesis and contributes to changes in energy expenditure that accompany changes in diet. The energy imbalance resulting from metabolic heat in response to cold exposure and to diet intake is covered by the sympathetic nervous system, which suggest an unequivocal relation between sympathetic activity and body fat deposition [ 71 ].
Even in healthy subjects body fat showed a direct relationship with SNS activity [ 72 ]. Grassi et al. evaluating normal control subjects, subjects with peripheral and central obesity showed a greater sympathetic activity in subjects with central obesity [ 73 ]. A recent study analyzed the effects of surgically-induced weight loss in severely obese patients and showed an important reduction in insulin resistance index, leptin levels, and sympathetic activity [ 74 ].
Abdominal adiposity loss is associated with diabetogenic and atherogenic markers. Different studies suggest a straight relationship between sympathetic activity and central WAT [ 66 , 73 ]. The relation is bidirectional; sympathetic denervation of WAT blocks lipolysis to a variety of lipolytic stimuli and the use of anterograde transneural viral tracers has defined the sensory input from WAT to the brain [ 76 ].
These experiments show the importance of sympathetic innervation in WAT. The effects of parasympathetic innervation of the adipose tissue are partially elucidated.
Kreier et al. used a retrograde transneuronal tracer, i. They demonstrated that parasympathetic denervation of WAT significantly reduced insulin-dependent glucose and free fat acid uptake and increased the sensitivity of lipase hormone-sensitive, resulting in an increased intracellular triglyceride breakdown.
Thus, evidence suggests that the parasympathetic system is associated with adipogenesis triglycerides synthesis , whereas the sympathetic system is associated with lipolysis triglycerides breakdown in WAT.
SNS modulation of visceral adipose tissue is related to different adrenergic receptors. Adipocyte plasma membranes express beta-1 β 1 , beta-2 β 2 , beta-3 β 3 , alpha-1 α 1 , and alpha-2 α 2 adrenergic receptors [ 78 ]. The balance between alpha and beta adrenergic receptors emerges as an important variable in regulating adipocyte cell number.
demonstrated adipocyte hyperplasia [ 79 ]. The fasting state is associated with adipolysis, which is modulated mainly by the β 3 adrenergic receptor. Conversely, adipogenesis is associated with activation of the parasympathetic system, but the receptor mediating adipogenesis is not well defined [ 76 ].
Thus, in addition to the well-known factors classically associated with VAS, the literature suggests an important role for autonomic activity in the regulation of WAT, which highlights the complex role of adipose tissue in the VAS.
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Tremaroli V, Bäckhed F. In obese mice, a liver enzyme travels to visceral fat and increases inflammation inflammatory cells labeled red , thereby promoting diabetes filled with cells. The photo on the right shows fat tissue from obese mice who have been given a drug that blocks the enzyme.
The fat that builds up deep in the abdomen—more than any other type of body fat—raises the risk of insulin resistance and type 2 diabetes. Researchers have known that abdominal fat becomes dangerous when it becomes inflamed but have had a hard time determining what causes the inflammation.
A new study at Columbia University Irving Medical Center CUIMC has revealed that at least one of the culprits for this mysterious inflammation comes from the liver. The researchers found that, in obese mice, the liver increases its production of an enzyme called DPP4. This enzyme travels through the blood stream to abdominal fat.
Once inside fat tissue, DPP4 helps to activate inflammatory cells. The good news is that this inflammation can be soothed by turning off DPP4 production in the liver, as the researchers demonstrated in mice.
And even though the animals remained obese, soothing inflamed abdominal fat improved their insulin resistance. Stock Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.
Current DPP4 inhibitors do not reduce inflammation in fat or improve insulin resistance. Many patients with type 2 diabetes are given oral DPP4 inhibitors known as gliptins to help manage their disease. These drugs lower blood sugar by preventing DPP4 from interfering with a hormone that stimulates insulin production.
But surprisingly, these drugs had no effect on inflammation in the abdominal fat of obese mice, the researchers found. The reason for this shortcoming of gliptins, Tabas believes, may be related to their effects in the gut versus the liver.
But we have some evidence that DPP4 inhibitors in the gut also end up promoting inflammation in fat.
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