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 central body fat distribution. Insulin resistance almost invariably occurs, and might be a major trigger for disease-generating mechanisms either directly or via generation of other disease precursors ("risk factors"). The hypothalamo-pituitary-adrenal (HPA) axis seems to be hypersensitive in abdominal obesity, a statement supported by increased responses to challenges from the adrenals to central regulatory centers. Furthermore, the feedback control by central glucocorticoid receptors, probably a secondary, functional consequence of an elevated HPA axis activity, because the receptor gene appears normal. Secretion of sex steroid and growth hormones is diminished, which might be consequence of elevated HPA axis activity. Hyperandrogenicity in women is probably of adrenal origin and another consequence of the sensitivity of the HPA axis. The endocrine abnormalities thus are periodically elevated cortisol and androgen (women) concentrations, as well as low secretions of gender-specific steroid and growth hormones. Since elevated cortisol, and low sex-steroid and growth hormone secretions, probably direct storage fat to visceral depots, the multiple endocrine abnormalities probably cause enlargement of these depots. Furthermore, these hormonal abnormalities most likely at least contribute to the creation of insulin resistance with additional effects of elevated fatty acids from central fat depots, which are sensitive to lipid mobilization agents. This chain of events indicates the central role of the hypersensitive HPA axis. Known causes of sensitization of this axis have been identified in subjects with abdominal obesity, including depression, anxiety, alcohol, and smoking. A common cause of HPA axis activation is perceived stress, with a depressive, defeatist, or "helplessness" reaction. In subjects with abdominal preponderance of body fat stores a number of psychosocial and socioeconomics handicaps have been identified, hypothetically predisposing to such reactions. In a primate model (monkeys), mild psychosocial stress is followed by identical psychological, endocrine, anthropometric, and metabolic abnormalities as in humans with abdominal preponderance of body fat stores, including early signs of diabetes and cardiovascular disease. These findings strongly support the interpretation that a stress reaction activating the HPA axis is involved also in the human syndrome. Interventions with normalization of the endocrine perturbations are followed by clear improvements of the multiple abnormalities in both clinical, experimental, cellular and molecular studies, suggesting that the pathogenesis of abdominal preponderance of body fat and its endocrine, anthropometric and metabolic abnormalities are indeed consequences of the endocrine abnormalities identified.