The metabolic syndrome

In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.

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Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis of Type 2 Diabetes

Excess intra-abdominal adipose tissue accumulation, often termed visceral obesity, is part of a phenotype including dysfunctional subcutaneous adipose tissue expansion and ectopic triglyceride storage closely related to clustering cardiometabolic risk factors. Hypertriglyceridemia; increased free fatty acid availability; adipose tissue release of proinflammatory cytokines; liver insulin resistance and inflammation; increased liver VLDL synthesis and secretion; reduced clearance of triglyceride-rich lipoproteins; presence of small, dense LDL particles; and reduced HDL cholesterol levels are among the many metabolic alterations closely related to this condition. Age, gender, genetics, and ethnicity are broad etiological factors contributing to variation in visceral adipose tissue accumulation. Specific mechanisms responsible for proportionally increased visceral fat storage when facing positive energy balance and weight gain may involve sex hormones, local cortisol production in abdominal adipose tissues, endocannabinoids, growth hormone, and dietary fructose. Physiological characteristics of abdominal adipose tissues such as adipocyte size and number, lipolytic responsiveness, lipid storage capacity, and inflammatory cytokine production are significant correlates and even possible determinants of the increased cardiometabolic risk associated with visceral obesity. Thiazolidinediones, estrogen replacement in postmenopausal women, and testosterone replacement in androgen-deficient men have been shown to favorably modulate body fat distribution and cardiometabolic risk to various degrees. However, some of these therapies must now be considered in the context of their serious side effects. Lifestyle interventions leading to weight loss generally induce preferential mobilization of visceral fat. In clinical practice, measuring waist circumference in addition to the body mass index could be helpful for the identification and management of a subgroup of overweight or obese patients at high cardiometabolic risk.

Pathophysiology of Human Visceral Obesity: An Update

The "metabolic syndrome" (MetS) is a clustering of components that reflect overnutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders. Because the MetS is a cluster of different conditions, and not a single disease, the development of multiple concurrent definitions has resulted. The prevalence of the MetS is increasing to epidemic proportions not only in the United States and the remainder of the urbanized world but also in developing nations. Most studies show that the MetS is associated with an approximate doubling of cardiovascular disease risk and a 5-fold increased risk for incident type 2 diabetes mellitus. Although it is unclear whether there is a unifying pathophysiological mechanism resulting in the MetS, abdominal adiposity and insulin resistance appear to be central to the MetS and its individual components. Lifestyle modification and weight loss should, therefore, be at the core of treating or preventing the MetS and its components. In addition, there is a general consensus that other cardiac risk factors should be aggressively managed in individuals with the MetS. Finally, in 2008 the MetS is an evolving concept that continues to be data driven and evidence based with revisions forthcoming.

The Metabolic Syndrome

The National Cholesterol Education Program’s Adult Treatment Panel III (ATP III) report [1] added the metabolic syndrome, a multidimensional risk factor for cardiovascular disease (CVD), as a coequal partner of elevated low-density lipoprotein (LDL) cholesterol for risk-reduction therapies. Interest in the metabolic syndrome has increased greatly since the publication of the ATP III report. There are several aspects to the metabolic syndrome that deserve consideration for clinical practice: 1) major clinical outcomes, 2) metabolic components, 3) pathogenesis, 4) clinical criteria for diagnosis, 5) risk for clinical outcomes, and 6) therapeutic interventions.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)66378-7.pdf

Differences in fat cell size and function among adipose tissue depots are well known and may be important in the pathophysiology of the metabolic and cardiovascular complications of obesity. Since the newly discovered adipocyte hormone leptin is thought to be a central factor in the regulation of energy homeostasis, it may be interesting to know if there are regional differences in leptin production. The aim of this study was to compare the level of leptin expression in the omental and subcutaneous abdominal adipose tissue from obese humans. Adipose tissue samples were collected from 25 severely obese adults (mean BMI: 48.9 +/- 9.7 kg/m2) undergoing vertical gastric banding. Semi-quantitative determination of leptin mRNA by the RT-PCR technique showed significantly lower leptin expression in omental compared to subcutaneous abdominal adipose tissue (leptin/Sp1 ratio in omental vs. subcutaneous fat: 1.53 +/- 0.89 vs. 3.02 +/- 1.58, p < 0.01). Identical results were obtained when Northern blotting was applied in a subgroup. Leptin expression increased with age in omental adipose tissue (r = 0.42, p < 0.05), but not in subcutaneous tissue. No correlation was found between BMI or waist/hip ratio (WHR) and leptin expression in omental or subcutaneous adipose tissue. The regional difference in leptin expression was similar in the patients with impaired glucose tolerance/type-2 diabetes and those with normal glucose tolerance. In conclusion, the results of this study indicate that leptin expression is lower in omental than subcutaneous adipose tissue, possibly due to differences in fat cell size and/or sympathetic innervation.

Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans.

Since evidence has appeared that tumor necrosis factor-alpha (TNF) is involved in the loss of body fat in the course of wasting diseases, a large number of studies have investigated the physiological role of this cytokine in adipose tissue. TNF treatment of several in vitro models of adipogenesis clearly showed that TNF is a potent inhibitor of adipose differentiation. This antiadipogenic property is accompanied by suppression of developmental and metabolic markers of fat cell differentiation, such as peroxisome proliferator-activated receptor (PPAR)-gamma2, lipoprotein lipase (LPL), glycerol-3-phosphate dehydrogenase (GPDH) and GLUT4. Moreover, TNF promotes lipolysis in mature adipocytes and, subsequently, a reversion of the adipocyte phenotype. Recent studies demonstrated that TNF directly interferes with the insulin signaling cascade at early steps and, thus, impairs insulin-stimulated glucose transport. Further progress in understanding the role of TNF in adipose tissue was made when endogenous TNF mRNA expression was demonstrated in adipose tissue. Obesity was found to represent a state of overexpression of the TNF system. Such findings support the hypothesis that TNF is a mediator of obesity-linked insulin resistance. However, this concept is mainly based on animal data and is so far only partially supported by studies in humans. Taken together, the results of a variety of experimental and clinical studies suggest that TNF may act as an important auto/paracrine regulator of fat cell function which serves to limit adipose tissue expansion, probably by inducing insulin resistance which may in turn cause metabolic disturbances. Elucidation of the molecular mechanisms of TNF production and action in adipose tissue may help to find new approaches for the treatment of insulin resistance in humans.

The role of TNF-alpha in human adipose tissue: prevention of weight gain at the expense of insulin resistance?

Tumor necrosis factor-alpha (TNF) is known to inhibit fat cell development in vitro and to be expressed in adipose tissue suggesting that it may act as an auto-/paracrine regulator of adipose tissue mass in vivo. We demonstrate here that endogenous TNF-mRNA expression of cultured human preadipocytes and adipocytes is suppressed by the unspecific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), which is frequently used to trigger the differentiation process. As assessed by the measurement of glycerophosphate dehydrogenase, IBMX stimulated the differentiation of human preadipocytes in a dose dependent manner up to threefold but remained ineffective when cells were simultaneously treated with 1 nM TNF. These results suggest that the adipogenic effect of IBMX is mediated by suppression of endogenous TNF production.

The phosphodiesterase inhibitor IBMX suppresses TNF-alpha expression in human adipocyte precursor cells: a possible explanation for its adipogenic effect.

F. Hube

Papers

Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans.

The role of TNF-alpha in human adipose tissue: prevention of weight gain at the expense of insulin resistance?

The phosphodiesterase inhibitor IBMX suppresses TNF-alpha expression in human adipocyte precursor cells: a possible explanation for its adipogenic effect.