Adiposity and Diabetes

• ADA, American Diabetes Association
• AMP, adenosine monophosphate
• apo, apolipoprotein
• CBS, cystathionine β-synthase
• CETP, cholesterol ester transfer protein
• CRP, C-reactive protein
• CVD, cardiovascular disease
• FFA, free fatty acid
• Hcs, homocysteine
• HSD, 11-β-hydroxysteroid dehydrogenase
• relm, resistin-like molecule
• HSP, Heparan sulfate proteoglycans
• IFG, impaired fasting glucose
• IL, interleukin
• IRAS, Insulin Resistance Atherosclerosis Study
• LPL, lipoprotein lipase
• MAP, mitogen-activated protein
• PAI, plasminogen activator inhibitor
• PI3K, phosphatidylinositol 3-kinase
• POMC, proopiomelanocortin
• PPAR, peroxisome proliferator-activated receptor
• RLPC, remnant-like particle cholesterol
• TNF, tumor necrosis factor
• TZD, thiazolidinedione
• WOSCOPS, West of Scotland Coronary Prevention Study

At a symposium titled “Adipose Tissue as a Secretory Organ” at the American Diabetes Association (ADA), San Francisco, June 2002, Jeffrey Flier (Boston, MA) discussed the effects of visceral obesity. While reviewing the differing components of the metabolic syndrome, which to large extent are driven by insulin resistance, he asked, “Where does the insulin resistance come from?” The existence of a common underlying factor related to visceral obesity, which is more strongly associated with the syndrome than total obesity, might be important. A role for abnormal glucocorticoid metabolism in adipose tissue as the mechanism of the syndrome would explain many of its features. Glucocorticoids regulate adipose tissue function and distribution and in excess produce Cushing’s syndrome, which is characterized by visceral obesity, insulin resistance, and diabetes. The prevalent forms of obesity, however, are not associated with increased circulating glucocorticoid levels. Flier pointed out that the adipocyte is an active endocrine cell that produces hormones, in particular leptin, cytokines, complement factors, and important enzymes, such as angiotensinogen. Cortisol, produced in the adrenal gland, acts on cellular glucocorticoid receptors but importantly shows metabolism within cells, with 11-β-hydroxysteroid dehydrogenase (HSD)-2 degrading cortisol into the inactive cortisone, while HSD-1 is a reductase that produces cortisol from cortisone.

The standard understanding of the hypothalamic pituitary adrenal axis is of negative feedback between cortisol and pituitary adrenocorticotropic hormone (ACTH) production, an incomplete model that does not take into account the pathways for activation and for inactivation of cortisol in a variety of cells. In the kidney, HSD-2 is critical to protect mineralocorticoid receptors from activation by circulating glucocorticoids, while HSD-1 in liver, adipose tissue, and brain leads to increased glucocorticoid action. HSD-1 is expressed to a greater extent in visceral adipose tissue, which also express greater levels of cortisol receptors. HSD-1 in adipose tissue may in …