Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones

Insulin resistance is a key metabolic defect in type 2 diabetes that is exacerbated by obesity, especially if the excess adiposity is located intra-abdominally/centrally. Insulin resistance underpins many metabolic abnormalities-collectively known as the insulin resistance syndrome-that accelerate the development of cardiovascular disease. Thiazolidinedione anti-diabetic agents improve glycaemic control by activating the nuclear receptor peroxisome proliferator activated receptor-gamma (PPARgamma). This receptor is highly expressed in adipose tissues. In insulin resistant fat depots, thiazolidinediones increase pre-adipocyte differentiation and oppose the actions of pro-inflammatory cytokines such as tumour necrosis factor-alpha. The metabolic consequences are enhanced insulin signalling, resulting in increased glucose uptake and lipid storage coupled with reduced release of free fatty acids (FFA) into the circulation. Metabolic effects of PPARgamma activation are depot specific-in people with type 2 diabetes central fat mass is reduced and subcutaneous depots are increased. Thiazolidinediones increase insulin sensitivity in liver and skeletal muscle as well as in fat, but they do not express high levels of PPARgamma, suggesting that improvement in insulin action is indirect. Reduced FFA availability from adipose tissues to liver and skeletal muscle is a pivotal component of the insulin-sensitising mechanism in these latter two tissues. Adipocytes secrete multiple proteins that may both regulate insulin signalling and impact on abnormalities of the insulin resistance syndrome--this may explain the link between central obesity and cardiovascular disease. Of these proteins, low plasma adiponectin is associated with insulin resistance and atherosclerosis--thiazolidinediones increase adipocyte adiponectin production. Like FFA, adiponectin is probably an important signalling molecule regulating insulin sensitivity in muscle and liver. Adipocyte production of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, and angiotensin II secretion are partially corrected by PPARgamma activation. The favourable modification of adipocyte-derived cardiovascular risk factors by thiazolidinediones suggests that these agents may reduce cardiovascular disease as well as provide durable glycaemic control in type 2 diabetes.     

Thematic review series: patient-oriented research. Free fatty acid metabolism in human obesity

Adipose tissue lipolysis provides circulating FFAs to meet the body's lipid fuel demands. FFA release is well regulated in normal-weight individuals; however, in upper-body obesity, excess lipolysis is commonly seen. This abnormality is considered a cause for at least some of the metabolic defects (dyslipidemia, insulin resistance) associated with upper-body obesity. "Normal" lipolysis is sex-specific and largely determined by the individual's resting metabolic rate. Women have greater FFA release rates than men without higher FFA concentrations or greater fatty acid oxidation, indicating that they have greater nonoxidative FFA disposal, although the processes and tissues involved in this phenomenon are unknown. Therefore, women have the advantage of having greater FFA availability without exposing their tissues to higher and potentially harmful FFA concentrations. Upper-body fat is more lipolytically active than lower-body fat in both women and men. FFA released by the visceral fat depot contributes only a small percentage of systemic FFA delivery. Upper-body subcutaneous fat is the dominant contributor to circulating FFAs and the source of the excess FFA release in upper-body obesity. We believe that abnormalities in subcutaneous lipolysis could be more important than those in visceral lipolysis as a cause of peripheral insulin resistance. Understanding the regulation of FFA availability will help to discover new approaches to treat FFA-induced abnormalities in obesity.     

Impact of different ectopic fat depots on cardiovascular and metabolic diseases

A growing body of evidence is pointing out the pathophysiological role of fat accumulation in different organs. Ectopic fat depots within heart, liver, skeletal muscle, kidney, and pancreas as well as around blood vessels might be more associated to cardiometabolic risk than classical variables, such as body mass index. Among different mechanisms, lipid metabolism appears to be particularly influenced by ectopic fat depots. Indeed, intracellular accumulation of nonesterified fatty acids, and triglycerides promotes endoplasmic reticulum stress, mitochondrial uncoupling, oxidative stress, and altered membrane composition/function, finally promoting inflammatory response and cell death. The dysfunctional adipose tissue was shown to induce both local and systemic effects, with relevant clinical consequences. Epicardial fat and myocardial steatosis have been associated with the development of atrial fibrillation and ventricular dysfunction. Similarly perivascular adipose tissue appears to trigger atherosclerosis and hypertension. Nonalcoholic fatty liver disease has been recognized both as the hepatic manifestation of metabolic syndrome and as a cardiovascular (CV) risk factor. Importantly, the renal sinus fat emerged as a potential player in kidney dysfunction. Finally, both skeletal muscle and pancreatic fat depots have been indicated as potential endocrine modulators of insulin resistance. Considering the global rise in the prevalence of obesity, the understanding of mechanisms underlying ectopic fat accumulation represents an urgent need, with potential clinical implications for CV risk stratification. Here, we attempt to update the current knowledge of the different ectopic fat depots, focusing on underlying mechanisms and potential clinical implications.     

Visceral fat and liver fat are independent predictors of metabolic risk factors in men

We examined the independent associations among abdominal adipose tissue (AT), liver fat, cardiorespiratory fitness (CRF), and lipid variables in 161 Caucasian men who had a wide variation in adiposity. We measured AT and liver fat by computed tomography and CRF by a maximal exercise test on a treadmill. Visceral AT remained a significant (P or= 0.05) correlate of any lipid variable after control for visceral AT and CRF. Furthermore, subdivision of subcutaneous AT into deep and superficial depots did not alter these observations. Visceral AT was the strongest correlate of liver fat and remained so after control for abdominal subcutaneous AT, CRF, and alcohol consumption (r = -0.34, P < 0.01). In contrast, abdominal subcutaneous AT and CRF were not significant (P > 0.10) correlates of liver fat after control for visceral AT. Visceral AT remained a significant (P < 0.01) correlate of TG, HDL-C, and TC/HDL-C independent of liver fat. However, liver fat was also a significant correlate (P 相似文献   

Adipose tissue metabolism -- an aspect we should not neglect?

Free fatty acids (FFAs) are the most metabolically important products of adipose tissue lipolysis. Experimentally creating high FFA concentrations can reproduce the metabolic abnormalities of obesity in lean, healthy persons and lowering FFA concentrations can improve the metabolic health of upper body obese individuals. FFA concentrations are determined by both the release of FFAs into the bloodstream and the clearance of FFAs from the bloodstream. Normal FFA release rates are different in men and women and total FFA release is closely linked to resting energy expenditure. Upper body subcutaneous fat, visceral fat, and leg fat depots contribute differently to the exposure of various tissues to FFAs. The implications of regional adipose tissue lipolysis to systemic FFA availability and the effect of different approaches to treatment of obesity are discussed.     

Obesity reduces methionine sulphoxide reductase activity in visceral adipose tissue

Visceral obesity is linked to insulin resistance and cardiovascular disease. A recent genetic study indicated that the gene locus for the anti-oxidant defense enzyme methionine sulphoxide reductase A (MsrA) is positively associated with the development of visceral adiposity. This work tested the hypothesis that Msr activity is diminished in visceral fat as a result of obesity. It used two animal models of obesity, wild-type rats fed a high-fat (45% of calories from fat) diet and Zucker rats fed a 10% fat calorie diet. The data indicate that MsrA activity was selectively reduced by ～ 25% in the visceral adipose, but not subcutaneous adipose or liver, of both rat models as compared to control, wild type rats receiving a 10% fat calorie diet. MsrB activity was similarly reduced only in visceral fat. The data indicate that Msr activity is reduced by obesity and may alter oxidative stress signalling of obesity.     

Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity

Central obesity is associated with insulin resistance and dyslipidemia. Thus, the mechanisms that control fat distribution and its impact on systemic metabolism have importance for understanding the risk for diabetes and cardiovascular disease. Hypercortisolemia at the systemic (Cushing's syndrome) or local levels (due to adipose-specific overproduction via 11β-hydroxysteroid dehydrogenase 1) results in the preferential expansion of central, especially visceral fat depots. At the same time, peripheral subcutaneous depots can become depleted. The biochemical and molecular mechanisms underlying the depot-specific actions of glucocorticoids (GCs) on adipose tissue function remain poorly understood. GCs exert pleiotropic effects on adipocyte metabolic, endocrine and immune functions, and dampen adipose tissue inflammation. GCs also regulate multiple steps in the process of adipogenesis. Acting synergistically with insulin, GCs increase the expression of numerous genes involved in fat deposition. Variable effects of GC on lipolysis are reported, and GC can improve or impair insulin action depending on the experimental conditions. Thus, the net effect of GC on fat storage appears to depend on the physiologic context. The preferential effects of GC on visceral adipose tissue have been linked to higher cortisol production and glucocorticoid receptor expression, but the molecular details of the depot-dependent actions of GCs are only beginning to be understood. In addition, increasing evidence underlines the importance of circadian variations in GCs in relationship to the timing of meals for determining their anabolic actions on the adipocyte. In summary, although the molecular mechanisms remain to be fully elucidated, there is increasing evidence that GCs have multiple, depot-dependent effects on adipocyte gene expression and metabolism that promote central fat deposition. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.     

Visceral obesity and the heart

Obesity and particularly its deleterious form, visceral adiposity, has reached a high prevalence in the industrialized world owing to the lack of exercise and the widely available energy-dense diet. As a consequence, cardiovascular diseases and metabolic disorders are afflicting an unprecedented number of individuals at a world-wide scale. Over the last decades, investigations have established firm links between visceral obesity and the development of cardiovascular diseases. Moreover, studies in the field of lipid partitioning have demonstrated that inadequacy of homeostatic mechanism ensuring adequate handling of energy surplus is associated with accumulation of visceral fat and lipid overload of internal organs, which are participating to the development of heart diseases. Visceral obesity and its metabolic consequences often referred to as the metabolic syndrome is associated with the production of an atherosclerosis prone milieu. In this review, clinical implications of visceral obesity on the development of cardiovascular disorders are reviewed along with important mechanisms participating to the development of these disorders. Implications and failure of lipid partitioning and some of the potential pathways mediating development of heart diseases are also covered in view of recent development of therapeutic options.     

microRNA‐379 couples glucocorticoid hormones to dysfunctional lipid homeostasis

In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR)‐379/410 genomic cluster as a key component of GC/GR‐driven metabolic dysfunction. Particularly, miR‐379 was up‐regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR‐dependent manner. Hepatocyte‐specific silencing of miR‐379 substantially reduced circulating very‐low‐density lipoprotein (VLDL)‐associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR‐379 effects on key receptors in hepatic TG re‐uptake. As hepatic miR‐379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR‐controlled miRNA cluster not only defines a novel layer of hormone‐dependent metabolic control but also paves the way to alternative miRNA‐based therapeutic approaches in metabolic dysfunction.     

Palmitate Induces Insulin Resistance in H4IIEC3 Hepatocytes through Reactive Oxygen Species Produced by Mitochondria

Visceral adiposity in obesity causes excessive free fatty acid (FFA) flux into the liver via the portal vein and may cause fatty liver disease and hepatic insulin resistance. However, because animal models of insulin resistance induced by lipid infusion or a high fat diet are complex and may be accompanied by alterations not restricted to the liver, it is difficult to determine the contribution of FFAs to hepatic insulin resistance. Therefore, we treated H4IIEC3 cells, a rat hepatocyte cell line, with a monounsaturated fatty acid (oleate) and a saturated fatty acid (palmitate) to investigate the direct and initial effects of FFAs on hepatocytes. We show that palmitate, but not oleate, inhibited insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 2 and serine phosphorylation of Akt, through c-Jun NH₂-terminal kinase (JNK) activation. Among the well established stimuli for JNK activation, reactive oxygen species (ROS) played a causal role in palmitate-induced JNK activation. In addition, etomoxir, an inhibitor of carnitine palmitoyltransferase-1, which is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation, as well as inhibitors of the mitochondrial respiratory chain complex (thenoyltrifluoroacetone and carbonyl cyanide m-chlorophenylhydrazone) decreased palmitate-induced ROS production. Together, our findings in hepatocytes indicate that palmitate inhibited insulin signal transduction through JNK activation and that accelerated β-oxidation of palmitate caused excess electron flux in the mitochondrial respiratory chain, resulting in increased ROS generation. Thus, mitochondria-derived ROS induced by palmitate may be major contributors to JNK activation and cellular insulin resistance.Insulin is the major hormone that inhibits gluconeogenesis in the liver. Visceral adiposity in obesity causes hepatic steatosis and insulin resistance. In an insulin-resistant state, impaired insulin action allows enhancement of glucose production in the liver, resulting in systemic hyperglycemia (1) and contributing to the development of type 2 diabetes. In addition, we have demonstrated experimentally that insulin resistance accelerated the pathology of steatohepatitis in genetically obese diabetic OLETF rats (2). In contrast, lipid-induced oxidative stress caused steatohepatitis and hepatic insulin resistance in mice (3). In fact, steatosis of the liver is an independent predictor of insulin resistance in patients with nonalcoholic fatty liver disease (4).It remains unclear whether hepatic steatosis causally contributes to insulin resistance or whether it is merely a resulting pathology. Excessive dietary free fatty acid (FFA)² flux into the liver via the portal vein may cause fatty liver disease and hepatic insulin resistance. Indeed, elevated plasma FFA concentrations correlate with obesity and decreased target tissue insulin sensitivity (5).Experimentally, lipid infusion or a high fat diet that increases circulating FFA levels promotes insulin resistance in the liver. Candidate events linking FFA to insulin resistance in vivo are the up-regulation of SREBP-1c (6), inflammation caused by activation of c-Jun amino-terminal kinase (JNK) (7) or IKKβ (8), endoplasmic reticulum (ER) stress (9), ceramide (10, 11), and TRB3 (12).However, which event is the direct and initial target of FFA in the liver is unclear. Insulin resistance induced by lipid infusion or a high fat diet is complex and may be accompanied by alterations not restricted to the liver, making it difficult to determine the contribution of FFAs to hepatic insulin resistance. For example, hyperinsulinemia and hyperglycemia secondary to the initial event also may contribute to the development of diet-induced insulin resistance in vivo (6).To address the early event(s) triggering the development of high fat diet- or obesity-induced insulin resistance, we investigated the molecular mechanism(s) underlying the direct action of FFA on hepatocytes to cause insulin resistance in vitro, using the rat hepatocyte cell line H4IIEC3. We found that mitochondria-derived reactive oxygen species (ROS) were a cause of palmitate-induced insulin resistance in hepatocytes.     

Free Fatty Acids,Lipopolysaccharide and IL-1α Induce Adipocyte Manganese Superoxide Dismutase Which Is Increased in Visceral Adipose Tissues of Obese Rodents

Excess fat storage in adipocytes is associated with increased generation of reactive oxygen species (ROS) and impaired activity of antioxidant mechanisms. Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme involved in detoxification of ROS, and objective of the current study is to analyze expression and regulation of MnSOD in obesity. MnSOD is increased in visceral but not subcutaneous fat depots of rodents kept on high fat diets (HFD) and ob/ob mice. MnSOD is elevated in visceral adipocytes of fat fed mice and exposure of differentiating 3T3-L1 cells to lipopolysaccharide, IL-1α, saturated, monounsaturated and polyunsaturated free fatty acids (FFA) upregulates its level. FFA do not alter cytochrome oxidase 4 arguing against overall induction of mitochondrial enzymes. Upregulation of MnSOD in fat loaded cells is not mediated by IL-6, TNF or sterol regulatory element binding protein 2 which are induced in these cells. MnSOD is similarly abundant in perirenal fat of Zucker diabetic rats and non-diabetic animals with similar body weight and glucose has no effect on MnSOD in 3T3-L1 cells. To evaluate whether MnSOD affects adipocyte fat storage, MnSOD was knocked-down in adipocytes for the last three days of differentiation and in mature adipocytes. Knock-down of MnSOD does neither alter lipid storage nor viability of these cells. Heme oxygenase-1 which is induced upon oxidative stress is not altered while antioxidative capacity of the cells is modestly reduced. Current data show that inflammation and excess triglyceride storage raise adipocyte MnSOD which is induced in epididymal adipocytes in obesity.     

Susceptibility to Development of Central Adiposity Among Populations

There is good evidence that central (visceral) adiposity is important in the development of the insulin resistance or metabolic syndrome (obesity, hyperinsulinemia, dyslipidemia, glucose intolerance, hypertension, and coronary heart disease). It is proposed that some non-Caucasian populations are especially susceptible to development of this syndrome, and that lifestyle changes may play important etiologic roles. We postulate that this is due to the presence in these populations of a genetic predisposition to weight gain, perhaps related to a “thrifty” genotype, leading to the concentration of weight gain in visceral fat depots, when there is exposure to conditions associated with westernization.     

Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice

Accumulation of visceral fat is a key phenomenon in the onset of obesity-associated metabolic disorders. Macrophage infiltration induces chronic mild inflammation widely considered as a causative factor for insulin resistance and eventually diabetes. We previously showed that >90% of macrophages infiltrating the adipose tissue of obese animals and humans are arranged around dead adipocytes, forming characteristic crown-like structures (CLS). In this study we quantified CLS in visceral and subcutaneous depots from two strains of genetically obese mice, db/db and ob/ob. In both strains, CLS were prevalent in visceral compared with subcutaneous fat. Adipocyte size and CLS density exhibited a positive correlation both in visceral and in subcutaneous depots; however, the finding that adipocyte size was smallest and CLS density highest in visceral fat suggests a different susceptibility of visceral and subcutaneous adipocytes to death. Visceral fat CLS density was 3.4-fold greater in db/db than in ob/ob animals, which at the age at which our experimental strain was used are more prone to glucose metabolic disorders.     

Neuregulin 4: A “Hotline” Between Brown Fat and Liver

The discovery that functional brown adipose tissue (BAT) in adult humans is inversely related to body fat mass and may reflect metabolic health has stimulated adipose tissue research to explore activation of BAT as a potential target for antiobesity treatments. In addition to the capacity of BAT to increase energy expenditure and glucose and lipid uptake, BAT secretes factors that may contribute to the regulation of whole‐body metabolism. Among signals released from BAT, neuregulin 4 (NRG4) has been recently identified as an endocrine factor that may link the activation of BAT to protection against diet‐induced obesity, insulin resistance, and hepatic steatosis. NRG4 was shown to directly reduce lipogenesis in hepatocytes, and it could indirectly activate BAT via sympathetic neurons or via inducing brown adipocyte–like signatures in white adipocytes in a paracrine manner. However, the potential relevance of NRG4 as a diagnostic tool or target for the treatment of obesity‐related diseases remains to be explored.     

Tissue leptin and plasma insulin are associated with lipoprotein lipase activity in severely obese patients

The development of metabolic complications of obesity has been associated with the existence of depot-specific differences in the biochemical properties of adipocytes. The aim of this study was to investigate, in severely obese men and women, both gender- and depot-related differences in lipoprotein lipase (LPL) expression and activity, as well as the involvement of endocrine and biometric factors and their dependence on gender and/or fat depot. Morbidly obese, nondiabetic, subjects (9 men and 22 women) aged 41.1+/-1.9 years, with a body mass index (BMI) of 54.7+/-1.7 kg/m(2) who had undergone abdominal surgery were studied. Both expression and activity of LPL and leptin expression were determined in adipose samples from subcutaneous and visceral fat depots. In both men and women, visceral fat showed higher LPL mRNA levels as well as lower ob mRNA levels and tissue leptin content than the subcutaneous one. In both subcutaneous and visceral adipose depots, women exhibited higher protein content, decreased fat cell size and lower LPL activity than men. The gender-related differences found in abdominal fat LPL activity could contribute to the increased risk for developing obesity-associated diseases shown by men, even in morbid obesity, in which the massive fat accumulation could mask these differences. Furthermore, the leptin content of fat depots as well as plasma insulin concentrations appear in our population as the main determinants of adipose tissue LPL activity, adjusted by gender, depot and BMI.     

Metabolic stress in insulin's target cells leads to ROS accumulation - a hypothetical common pathway causing insulin resistance

The metabolic syndrome is a cluster of cardiovascular risk factors, and visceral adiposity is a central component that is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. It is likely that adipose tissue, particularly in the intra-abdominal depot, is part of a complex interplay involving several tissues and that dysregulated hormonal, metabolic and neural signalling within and between organs can trigger development of metabolic disease. One attractive hypothesis is that many factors leading to insulin resistance are mediated via the generation of abnormal amounts of reactive oxygen species (ROS). There is much evidence supporting that detrimental effects of glucose, fatty acids, hormones and cytokines leading to insulin resistance can be exerted via such a common pathway. This review paper mainly focuses on metabolic and other 'stress' factors that affect insulin's target cells, in particular adipocytes, and it will highlight oxidative stress as a potential unifying mechanism by which these stress factors promote insulin resistance and the development and progression of type 2 diabetes.     

Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates

Dietary and xenobiotic compounds can disrupt endocrine signaling, particularly of steroid receptors and sexual differentiation. Evidence is also mounting that implicates environmental agents in the growing epidemic of obesity. Despite a long-standing interest in such compounds, their identity has remained elusive. Here we show that the persistent and ubiquitous environmental contaminant, tributyltin chloride (TBT), induces the differentiation of adipocytes in vitro and increases adipose mass in vivo. TBT is a dual, nanomolar affinity ligand for both the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor gamma (PPARgamma). TBT promotes adipogenesis in the murine 3T3-L1 cell model and perturbs key regulators of adipogenesis and lipogenic pathways in vivo. Moreover, in utero exposure to TBT leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and results in increased epididymal adipose mass in adults. In the amphibian Xenopus laevis, ectopic adipocytes form in and around gonadal tissues after organotin, RXR, or PPARgamma ligand exposure. TBT represents, to our knowledge, the first example of an environmental endocrine disrupter that promotes adipogenesis through RXR and PPARgamma activation. Developmental or chronic lifetime exposure to organotins may therefore act as a chemical stressor for obesity and related disorders.     

Higher Free Fatty Acid Uptake in Visceral Than in Abdominal Subcutaneous Fat Tissue in Men

Visceral adipose tissue has been shown to have high lipolytic activity. The aim of this study was to examine whether free fatty acid (FFA) uptake into visceral adipose tissue is enhanced compared to abdominal subcutaneous tissue in vivo. Abdominal adipose tissue FFA uptake was measured using positron emission tomography (PET) and [¹⁸F]‐labeled 6‐thia‐hepta‐decanoic acid ([¹⁸F]FTHA) and fat masses using magnetic resonance imaging (MRI) in 18 healthy young adult males. We found that FFA uptake was 30% higher in visceral compared to subcutaneous adipose tissue (0.0025 ± 0.0018 vs. 0.0020 ± 0.0016 µmol/g/min, P = 0.005). Visceral and subcutaneous adipose tissue FFA uptakes were strongly associated with each other (P < 0.001). When tissue FFA uptake per gram of fat was multiplied by the total tissue mass, total FFA uptake was almost 1.5 times higher in abdominal subcutaneous than in visceral adipose tissue. In conclusion, we observed enhanced FFA uptake in visceral compared to abdominal subcutaneous adipose tissue and, simultaneously, these metabolic rates were strongly associated with each other. The higher total tissue FFA uptake in subcutaneous than in visceral adipose tissue indicates that although visceral fat is active in extracting FFA, its overall contribution to systemic metabolism is limited in healthy lean males. Our results indicate that subcutaneous, rather than visceral fat storage plays a more direct role in systemic FFA availability. The recognized relationship between abdominal visceral fat mass and metabolic complications may be explained by direct effects of visceral fat on the liver.     

Adipokine genetics: Unbalanced protein secretion by human adipose tissue as a cause of the metabolic syndrome

Subcutaneous and visceral adipose compartments act, not only as fatty acid depots, but also as active endocrine organs that undergo hyperplastic changes and significantly enhance their function in obesity. Adipokines and other proteins secreted by both adipocytes and stromal cells play a central role in peripheral insulin resistance and the metabolic syndrome (MS). Minor alleles of the adipokine genes substantially contribute to MS. The most important consequence of MS is low-level systemic inflammation supported by adiposespecific synthesis of proinflammatory soluble molecules. Proinflammatory signals are secreted into the bloodstream and spread to peripheral tissues that express their receptors. The signals provided by adipose tissue stimulate the development of secondary complications of MS, including cardiovascular disorders (CVDs) and nonalcoholic fatty liver disease. The review describes the physiological effects of adiponectin, leptin, resistin, visfatin, and apelin and the influence of the minor alleles of the adipokine genes on the development of the secondary complications of MS.