A REGULATORS LOOP BETWEEN THE HYPOTHALAMO-PITUITARY-ADRENAL (HPA) AXIS AND CIRCULATING LEPTIN - A PHYSIOLOGICAL-ROLE OF ACTH

The product of the ob/ob gene, leptin, is known to be able to exert a modulatory role on HPA asis function. The aim of the present study was to determine whether endogenous ACTH and glucocorticoids exert any re gulatory effect on leptin secretion. For this purpose bilaterally adre nalectomized (ADX) or sham operated (Sham) adult male rats were implan ted with an indwelling i.v. catheter. A subgroup of ADX animals receiv ed, at the same time of surgery. a s.c. corticosterone (B) pellet (75 mg) (ADX+B). All animals were subjected to experimental designs 7 days after surgery. Our results indicate, as expected, that 7-day ADX anim als have several fold increased basal ACTH plasma levels and non detec table circulating B, whereas ADX+B rats showed basal plasma ACTH level s in the range of Sham values and plasma B concentrations of about 5 m u g/dl. interestingly, basal plasma leptin levels were significantly ( P < 0.05) decreased by 7 days post ADX, and B replacement therapy (ADX +B) restored circulating leptin to Sham levels. Acute dexamethasone (D xm; 30 mu g/kg body weight, i.v.) treatment induced a very rapid decre ase in plasma ACTH concentrations in both Sham and ADX rats, as well a s a decrease in plasma B levels in Sham rats. Interestingly, Dsm test had no effect on plasma leptin levels in Sham animals; however, in ADX rats. the synthetic glucocorticoid increased plasma leptin concentrat ions, restoring the levels observed in Sham rats. This effect occurred at the same time when plasma ACTH levels were decreasing toward basal Sham values. These results clearly indicate that, beside the known ef fects of leptin on HPA axis function, circulating ACTH and glucocortic oid are able to modulate leptin secretion in plasma. The lack of circu lating glucocorticoid and/or increased plasma ACTH concentrations, are responsible for decreasing leptin output, whereas decreased plasma AC TH concentrations allow an increase of leptin secretion in blood. Our data strongly support the existence of a closed, bi-directional. circu it between HPA axis function and adipose tissue metabolism, They furth er indicate the physiological relevance of different types of stress a ssociated with many phenotypes of obesity.