Is Adipose tissue a storage center or an endocrine organ? Eric S. Freedland, MD, Boston University School of Medicine explains why this is true in part 2 of his series: Role Of A Critical Visceral Adipose Tissue Threshold (CVATT) In Metabolic Syndrome:
Role of A Critical Visceral Adipose Tissue Threshold (CVATT) In Metabolic Syndrome:
Implications for Controlling Dietary Carbohydrates
Eric S. Freedland, MD
Boston University School of Medicine
Adipose Tissue As An Endocrine Organ
Once thought to be an inert energy storage depot, adipose tissue is now known to be a critical endocrine organ. The term “adipocytokines” or “adipokines” has been used to describe the numerous adipocyte secretory products which include: adiponectin, adipsin, estrogen, angiotensin II, angiotensinogen, leptin, plasminogen activator I (PAI-1), agouti protein, resistin , acylation stimulating protein (ASP), bone morphogenic protein (BMP), prostaglandins, insulin-like growth factor-1 (IGF-1), and various IGF binding proteins, tumor necrosis factor alpha (TNFα), interleukins (ILs), transforming growth factor (TGF)-B , and fibroblasts, as well as free fatty acids (FFAs) themselves. Adipokines such as IL-6 and PAI-1 are more highly secreted by VAT than abdominal SCAT, while leptin is more highly secreted by SCAT . Adipokines from VAT can be delivered via the portal system directly to the liver where they can affect hepatic, and ultimately systemic, inflammation. In an ex vivo study, VAT released greater amount of IL-6 and PAI-1 compared with abdominal SCAT .
Adiponectin has many beneficial vascular and metabolic effects, e.g., it serves as an anti-inflammatory molecule for vascular walls as well as adipose tissue, inhibits vascular smooth muscle proliferation, protects endothelium from macrophage adhesion and macrophage-induced injury , may increase fatty acid oxidation in peripheral tissues , protects against ectopic fat storage and has been linked with insulin sensitivity .
Ironically, although produced by adipose tissue, adiponectin levels are lowered with greater degrees of obesity and with overfeeding. Decreased concentrations of adiponectin are associated with type 2 diabetes, hypertension, elevated glucose levels, insulin and TGs, and cardiovascular disease (CVD). It has been suggested that adiponectin is under feedback inhibition in obesity and reduced in patients with metabolic syndrome . Adiponectin mRNA and protein levels have been found to be reduced in omental VAT compared with SCAT , and VAT may also produce an as-yet-identified factor that destabilizes adiponectin mRNA . The strong inverse correlation between serum adiponectin levels and VAT mass may in part explain the link between VAT and metabolic syndrome . Over 90 percent of the adipokines released by adipose tissue, except for adiponectin and leptin, could be attributed to non-fat cells, e.g., macrophages, retained in the adipose tissue matrix .
Implications of fat mass expansion
Fat mass can expand in one of two ways: individual adipocytes can increase in volume or they can increase in number as more are derived from preadipocytes. As adipocytes grow larger, they become dysfunctional. The total number of adipocytes is increased with increasing fat mass, but it is the increased number and percentage of large adipocytes, compared to the smaller ones, that may partially account for the inability of adipose tissue to function properly . While the smaller adipose cells tend to be more insulin sensitive, large adipocytes become insulin resistant and contribute more to the metabolic problems associated with obesity .
Preadipocytes from the SCAT depots have a greater differentiation capacity than those from the VAT depots . The differentiation of preadipocytes into lipid-storing adipocytes is regulated in part by the nuclear hormone receptor, peroxisome proliferator activated receptor (PPAR). Activation of this receptor by natural ligands, such as prostaglandin metabolites, or synthetic ligands, such as thiazolidinediones (TZDs), leads to stimulation of the differentiation pathway . This increases the number of smaller adipocytes in SCAT with a high avidity for fatty acid (FA) and TG uptake. These increased adipose stores made up of new, smaller, more insulin sensitive adipocytes act as a sink or powerful ‘buffers,’ avidly absorbing circulating fatty acids and triglycerides in the postprandial period. This prevents their diversion to non-adipose tissues, thereby protecting against ectopic fat syndrome and metabolic syndrome. It has been proposed that an inability to differentiate new adipocytes to accommodate and store excess energy, underlies the development of type 2 diabetes .
A thiazolidinedione (TZD) paradox
TZDs can increase the number of new fat cells, and because obesity is a major cause of insulin resistance, this represents an apparent paradox. Ex-vivo studies of human preadipocytes from SCAT and VAT depots have demonstrated that TZD-stimulated differentiation is much greater in SCAT than VAT preadipocytes . Since TZDs selectively promote adipogenesis in SCAT and not VAT, this would encourage the redistribution of body fat away from “harmful” VAT sites and toward “safer” SCAT ones . Thus, in this way, TZDs could allow for pushing the patient to below his CVATT. Paradoxically, the TZDs can lead to weight gain while improving insulin sensitivity as the new SCAT adipocytes continue to trap FA and as fat storage continues, eventually the new adipocytes will enlarge, become less insulin sensitive, and ultimately contribute to insulin resistance . TZDs may also exert anti-inflammatory effects on adipocytes by reducing the production of serum amyloid A (SAA) and preventing the TNFα-mediated expression of adiponectin production .
Macrophages increase their accumulation within fat depots in direct proportion to increases in adipose tissue and adipocyte size. The increased macrophage activity observed in the adipose tissue of the obese may reflect a combination of conversion of local preadipocytes to macrophages and activation and recruitment of resident macrophages and circulating monocytes. This seems to occur after the onset of adiposity but prior to insulin resistance, and supports the notion that pathophysiological consequences of obesity involve macrophages and inflammation that contribute to insulin resistance and metabolic syndrome . Evidence suggests that macrophages and adipocytes not only express overlapping sets of genes and serve similar functions, but also commingle in the same part of the body—the fat tissue .
VAT Versus SCAT (See Figure 2)
There are numerous inherent differences between VAT and SCAT. VAT is a major predictor for insulin resistance and metabolic syndrome . Compared to SCAT, VAT adipocytes have a higher rate of lipolysis, which is more readily stimulated by catecholamines and less readily suppressed by insulin . VAT also produces more IL-6 and plasminogen activator inhibitor-1 (PAI-1) . The “Portal Theory” suggests that insulin resistance and many of its related features could arise from VAT delivering free fatty acids (FFAs) at a high rate to the liver via the portal vein into which VAT directly drains . This, in turn, would increase hepatic glucose production, reduce hepatic insulin clearance, and ultimately lead to insulin resistance, hyperinsulinemia, hyperglycemia as well as non-alcoholic fatty liver disease (NAFLD). FFA flux could also lead to enhanced production of triglycerides (TGs) and apolipoprotein B-rich lipoproteins, which are features of the insulin resistance syndrome . Delivery of VAT derived pro-inflammatory cytokines may contribute to hepatic pathology such as non-alcoholic steatohepatitis (NASH). VAT also releases a large amount of glycerol which enters the liver where it can be converted to glucose, thereby contributing to hyperglycemia . It is likely that the relationship observed between VAT and metabolic complications may not exclusively result from FFA flux from VAT into the portal vein and the portal theory does not adequately hold up as the sole explanation of the role of VAT in metabolic syndrome .
VAT has twice the glucose uptake rate as SCAT
Recently, omental VAT cells have been shown to have an approximately two-fold higher rate of insulin-stimulated glucose uptake compared with SCAT adipocytes, and this could be explained by a higher GLUT-4 expression . Perhaps in situations with a high intake of dietary glycemic load, a higher rate of glucose uptake and subsequently lipogenesis might be one mechanism by which TGs are stored preferentially in the VAT depot. VAT is highly lipolytic and resistant to insulin’s lipogenic effects yet apparently can remain insulin sensitive to glucose uptake. This efficiency in glucose uptake may reflect VAT’s ability to accumulate and maintain its activity. Enhanced glucose utilization in VAT would be accompanied by less lipid oxidation, which would indirectly promote TG storage .
VAT has a high density of androgen receptors and testosterone which can amplify its own effect by up-regulation of androgen receptors, inhibiting the expression of lipoprotein lipase (LPL) and FA uptake . In men, VAT is strongly negatively correlated with plasma total and free testosterone and sex-hormone binding globulin (SHBG) concentrations. Thus, in young men whose plasma total testosterone and free testosterone are high, the amount of VAT is low. As men age, exceed their 20s, and reach middle age, their total and free testosterone decline, more fat is deposited in VAT stores, they often develop the “pot belly,” and their risk for CHD increases . The effects of testosterone on insulin resistance and metabolic syndrome risk factors are opposite in men and women . Testosterone production often declines in women as they age, but VAT obesity in women is associated with elevated levels of total testosterone, free testosterone, and SHBG . Hyperandrogenicity can also occur in polycystic ovary syndrome, where hyperinsulinemia can stimulate ovarian androgen production and suppress serum SHBG . While weight loss in both sexes has been consistently shown to reverse the abnormalities in testosterone levels , a number of placebo controlled studies have consistently demonstrated that administering testosterone to obese men resulted in a significant reduction in VAT. This occurred without significantly altering amounts of total body fat or lean body mass . However, the use of testosterone for VAT obesity is left open to debate .
11-β-Hydroxydehydrogenase1 (11-β HSD1)
Patients with type 2 diabetes and metabolic syndrome often appear Cushingoid, yet they invariably do not have elevated plasma cortisol . Compared to SCAT, VAT has more glucocorticoid receptors . The enzyme 11-β hydroxysteroid dehydrogenase type 1 (11-β HSD1) converts inactive cortisone to the active compound cortisol, and, if overexpressed, may cause increases in local cortisol concentrations . Local production of active cortisol from inactive cortisone driven by 11-β-HSD-1 activity is very high in VAT and barely detectable in SCAT. Therefore it is likely that the VAT depot actively contributes to the production of high local concentrations of cortisol, which might not be reflected by plasma levels. These, in turn, might contribute to an increase in VAT accumulation . 11-βHSD1 inhibition holds promise as a therapeutic target for VAT-associated metabolic syndrome .
VAT and impaired skeletal muscle oxidation
The amount of fat deposited within skeletal muscle (intramyocellular lipid—IMCL) and the ability of muscle to oxidize fat are important determinants of weight gain, weight regain following weight loss , and the development of insulin resistance syndrome . IMCL and the VAT depot might not be independent from each other. Furthermore, the relationship between IMCL and insulin sensitivity is independent of percent total body fat and SCAT but not of VAT . In individuals with type 2 diabetes, among the depots of regional and overall adiposity, VAT was the depot of adipose tissue that was most strongly related to skeletal muscle insulin resistance .
Colberg et al studied the fasting patterns of skeletal muscle fatty acid uptake and oxidation in healthy, lean and obese premenopausal women who had a cross-sectional VAT area over a range from 18 to 180 cm2 and BMIs from 19 to 39 kg/m2 . The researchers found that insulin sensitivity as well as postabsorptive rates of FFA utilization or oxidation by muscle were diminished in relation to VAT. Women with increased VAT did not have lower plasma FFA levels or lower rates for appearance of FFA, yet they had an impaired or reduced uptake of plasma FFA by the skeletal muscle in the leg . Together, this supports a role for VAT, IMCL lipid deposition, and perhaps impaired oxidation of nonadipose tissue lipid in insulin resistance and metabolic syndrome.
VAT may influence central SCAT
Mauriege et al found that adrenoreceptor sensitivity was increased in SCAT cells of individuals who have a higher VAT accumulation compared to those with a low VAT deposition . SCAT adipocytes from women with visceral obesity exhibit higher lipolysis rates in vitro than those obtained from women with little VAT . Mauriege et al also demonstrated that among men with high levels of VAT, SCAT adipocytes are more sensitive to β-adrenergic lipolysis which may further exacerbate an impaired insulin action, a potentially important factor in the etiology of metabolic syndrome associated with visceral obesity . Moreover, an increased truncal SCAT mass and an increased amount of VAT mass can independently predict insulin resistance . Together, these findings support that VAT may enhance central SCAT lipolysis and accelerate release of peripheral FFAs.
The PPARs are important transcription factors that play an important role in the induction of adipose-specific genes, the proliferation and differentiation of adipocytes, and the development of mature adipose tissue. A number of transcription factors are involved, including PPARγs. Giusti et al suggest that in VAT, the expression of PPARγ2 is controlled by local transcription factors (RXRα, αSREBP1, and SREBP1c) promoting fat storage in adipocytes. Given that the fat storage capacity is limited in VAT, RXRα induces the expression of PPARγ2 in SCAT to increase its overall capacity . These data also suggest that the signal to promote fat storage may occur in VAT and that other metabolic and hormonal factors are involved in the control and modulation of adipogenesis in visceral fat .
Perhaps the above can be explained as follows. SCAT cells may act as a buffer or sink for circulating FAs and TGs but once they reach their capacity they lose their protective benefits. Initially, VAT may influence SCAT to expand and act as a buffer. However, once the critical VAT threshold (CVATT) is achieved and metabolic syndrome has begun to develop, then VAT may influence central SCAT to become more VAT-like, i.e., more lipolytic and less sensitive to insulin’s adipogenic or lipid storing effects.
Next time more on SCAT
Eric S. Freedland, MD graduated from University of Rochester School of Medicine in 1982, trained in internal medicine at Mt. Auburn Hospital in Cambridge, MA, and emergency medicine at Harbor-UCLA Medical Center in Torrance, CA, and has held faculty positions at Harvard Medical School (1990-1991) and Boston University School of Medicine (1992-2004). Dr. Freedland has developed a nutrition-centered model of disease with a special emphasis on diabetes. A staunch advocate for prescribing lifestyle changes before drugs, Dr. Freedland has written and lectured extensively on this subject.
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