Adiposity and diabetes.

A t 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-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 fact promote visceral obesity. The initial recognizers of this phenomenon characterized visceral obesity as “Cushing’s disease of the omentum” (1). A transgenic model overexpressing rat HSD-1 in mouse visceral fat shows central obesity with particular increase in mesenteric fat, with cell size rather than cell number increasing. Circulating levels of corticosterone, the active glucocorticoid in rodents, are normal, but visceral fat corticosterone levels are increased. The mice have hyperphagia. Increased free fatty acid (FFA), triglyceride, and leptin levels are seen, with glucose intolerance, particularly when given high-fat diets, and extreme insulin resistance. Telemetry blood pressure measurements show development of hypertension as well, particularly on high-salt and highfat diets, with response to low-dose angiotensin receptor antagonist treatment. The increased blood pressure may be caused in part by the insulin-resistant state, but also of importance is the induction of adipose tissue angiotensinogen production, which is regulated by circulating glucocorticoids. Adipocyte angiotensinogen doubles, with increased circulating levels. Aldosterone levels are increased, while renin appears to be decreased. Levels of adiponectin are decreased in these animals, while tumor necrosis factor (TNF)increases. Other models of increased angiotensinogen expression lead to hypertension, further increasing the plausibility of this model. Flier concluded that there might be an “intracrine” rather than an endocrine cause of the insulin resistance syndrome, with increased HSD-1, thereby leading to local increases in cortisol producing adipogenesis and lipogenesis, induction of insulin resistance, and modification of a number of secreted adipocyte proteins contributing to the metabolic syndrome. A study on humans with fat biopsy suggests potential clinical relevance, with increased HSD-1 associated with obesity (2). More understanding of the regulation of HSD-1 is critical, and the development of specific HSD-1 inhibitors may lead to novel approaches to treatment. Interestingly, thiazolidinediones (TZDs) inhibit the activity of the enzyme. Flier described mice not expressing HSD-1 that are resistant to development of obesity and diabetes and also showed resistance to agerelated cognitive decline, thus suggesting potential for clinical use. An interesting question asked by an audience member was whether individuals who have undergone adrenalectomy and are treated with noncortisol glucocorticoids not metabolized by HSD-1 might be less likely than those receiving cortisol to develop the metabolic syndrome. In a study presented at the ADA meeting, Yu et al. [1700-P] found 7% lesser increases in food intake and body weight, a 28% lesser increase in epididymal fat pad weight, and 33 and 24% lower serum leptin and triglyceride levels, respectively, after injecting an antisense oligonucleotide to murine HSD-1 mRNA versus saline twice weekly in a model of high-fat diet–induced obesity, although glucose tolerance did not improve (abstract numbers refer to the abstracts of the 62nd ADA Scientific Sessions, Diabetes 51 [Suppl. 2], 2002). Alberts et al. [172-OR] reported studies with a selective inhibitor of HSD-1 in an animal model of type 2 diabetes, showing a decrease in blood glucose with a decrease in hepatic glucose ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●