Visceral Fat Deposits and the Metabolic Syndrome
Obesity is associated with many adverse health effects, including an increased risk of diabetes and heart disease. The combined condition of obesity, diabetes and heart disease is sometimes referred to as the metabolic syndrome. One of the factors that best correlates obesity with the rest of the metabolic syndrome is not overall body mass, but the distribution of adipose tissue in the abdominal region, visceral obesity. Glucocorticoids have been associated as a risk factor for the metabolic syndrome, but most obese individuals have normal levels of circulating corticosteroids. Active corticosteroids such as cortisol and corticosterone activate the glucocorticoid receptor, a nuclear hormone receptor and transcription factor. Obese individuals have elevated levels in adipose tissue of a key enzyme in glucocorticoid metabolism, 11beta hydroxysteroid dehydrogenase type 1 (11betaHSD-1). 11betaHSD-1 interconverts inactive corticosteroids and the active form. When present in cells, 11betaHSD-1 can convert inactive corticosteroids from the blood to create locally high concentrations in a tissue such as adipose tissue. When activated in adipose tissue, GR increases the level of visceral fat, induces insulin resistance and dyslipidemias that increase the risk of heart disease. The mechanisms by which GR might induce the various aspects of the metabolic syndrome are a key area of research. One of the genes activated by GR is lipoprotein lipase. When GR is activated in visceral adipose tissue, it will increase the expression of lipoprotein lipase (LPL). This enzyme hydrolyzes triglycerides in plasma, releasing free fatty acids into tissues, where they can be reassembled into triglycerides. In visceral adipose, this GR-driven overexpression of lipoprotein lipase will result in the increased deposits of visceral fat that are observed. Genes thought to be involved in insulin resistance also appear to be affected by altered 11betaHSD-1 corticosteroid metabolism in visceral fat. This includes downregulation of resistin and adipoQ, and induction of TNF-alpha. The elevated free fatty acids and active corticosteroids released from visceral fat may account for the metabolic changes in liver associated with the metabolic syndrome. Antidiabetic thiazoidinedione drugs such as troglitazone and Avandia act as agonists of another nuclear receptor, PPAR-gamma. These drugs activate PPAR-gamma and repress expression of 11betaHSD-1 in visceral tissue, perhaps accounting in part for the antidiabetic insulin sensitizing properties of these drugs.
Contributor:
REFERENCES: Combs, T.P. et al. (2002) Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology 143(3), 998-1007 E. Rask, et al. (2001) Tissue-Specific Dysregulation of Cortisol Metabolism in Human Obesity. J. Clin. Endocrinol. Metab. 86, 1418 Gura, T. (2001) Obesity research. Pot-bellied mice point to obesity enzyme. Science 294(5549), 2071-2 Masuzaki H. et al. (2001) A transgenic model of visceral obesity and the metabolic syndrome. Science 294(5549), 2166-70 Y. Kotelevtsev, et al. (1997) 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. PNAS U.S.A. 94, 14924
