BODY-FAT DISTRIBUTION, INSULIN-RESISTANCE, AND METABOLIC DISEASES

Obesity has now developed into a world-wide epidemic and is associated with large economic costs and prevalent diseases, particularly with c entral body fat distribution. Insulin resistance almost invariably occ urs, and might be a major trigger for disease-generating mechanisms ei ther directly or via generation of other disease precursors (''risk fa ctors''). The hypothalamo-pituitary-adrenal (HPA) axis seems to be hyp ersensitive in abdominal obesity, a statement supported by increased r esponses to challenges from the adrenals to central regulatory centers . Furthermore, the feedback control by central glucocorticoid receptor s is blunted, probably a secondary, functional consequence of an eleva ted HPA axis activity, because the receptor gene appears normal. Secre tion of sex steroid and growth hormones is diminished; which might be a consequence of elevated HPA axis activity. Hyperandrogenicity in wom en is probably of adrenal origin and another consequence of the sensit ivity of the HPA axis. The endocrine abnormalities thus are periodical ly elevated cortisol and androgen (women) concentrations, as well as l ow secretions of gender-specific steroid and growth hormones. Since el evated cortisol, and low sex-steroid and growth hormone secretions, pr obably direct storage fat to visceral depots, the multiple endocrine a bnormalities probably cause enlargement of these depots. Furthermore, these hormonal abnormalities most likely at least contribute to the cr eation of insulin resistance with additional effects of elevated fatty acids from central fat depots, which are sensitive to Lipid mobilizat ion agents. This chain of events indicates the central role of the hyp ersensitive HPA axis. Known causes of sensitization of this axis have been identified in subjects with abdominal obesity, including depressi on, anxiety, alcohol, and smoking. A common cause of HPA axis activati on is perceived stress, with a depressive, defeatist, or ''helplessnes s'' reaction. In subjects with abdominal preponderance of body fat sto res a number of psychosocial and socioeconomic handicaps have been ide ntified, hypothetically predisposing to such reactions. In a primate m odel (monkeys), mild psychosocial stress is followed by identical psyc hological, endocrine, anthropometric, and metabolic abnormalities as i n humans with abdominal preponderance of body fat stores, including ea rly signs of diabetes and cardiovascular disease. These findings stron gly support the interpretation that a stress. reaction activating the HPA axis is involved also in the human syndrome. Interventions with no rmalization of the endocrine perturbations are followed by clear impro vements of the multiple abnormalities in both clinical, experimental, cellular and molecular studies, suggesting that the pathogenesis of ab dominal preponderance of body fat and its endocrine, anthropometric an d metabolic abnormalities are indeed consequences of the endocrine abn ormalities identified. (C) Elsevier Science Inc. 1997.