Hypothalamic obesity: a pivotal role of endogenous glucocorticoid

Abstract

It is known that the neonatal treatment of rats with monosodium L-glutamate (MSG) induces several metabolic and hormonal abnormalities, resulting in enhanced adiposity and hyperleptinemia, among others. Our studies explored the consequences of MSGinduced enhanced hypothalamo-pituitary-adrenal (HPA) axis function and chronic hyperleptinemia on the adrenal sensitivity to the inhibitory effect of exogenous leptin. In addition, in this chapter includes the consequences of adrenal gland manipulations on several characteristics of the hypothalamic obese phenotype. Neonatal male rats treated with MSG or vehicle (controls, CTR) were followed during 150 days in order to study changes observed over development in body weight, food consumption as well as in vivo HPA axis and adipocyte functions. During adulthood, adrenal response to adrenocorticotropin (ACTH) was evaluated both in vitro and in vivo in order to determine the adrenal sensitivity to the inhibitory effect of leptin. For this purpose, sham operated as well as CTR and MSG rats with bilateral adrenal enucleation (AE) were used. Finally, by studying AE and bilaterally adrenalectomized (ADX) adult rats, either receiving corticosterone replacement therapy or not, we addressed modifications on both neuroendocrine-metabolic functions and adiposity depots. Our results indicate that: 1) between 30 and 150 days of age, MSG animals developed hypophagia, accompanied by arrest in body weight gain, and concomitant enhanced basal levels of all HPA axis components and of leptin; 2) adrenals from of 150 day-old MSG rats displayed an in vitro adrenocortical hyperresponse to ACTH stimulation as well as an adrenal refractoriness to the physiological inhibitory effect of leptin on ACTH-stimulated glucocorticoid output; and 3) bilateral adrenal enucleation (AE) in adult MSG-treated rats transiently reversed the MSG-induced hyperleptinemia, restoring normal leptin levels as well as a normal adrenal sensitivity to the inhibitory effect of leptin. While 21 days of either ADX or AE blunted enlarged adiposity mass in MSG rats, corticosterone replacement therapy in ADX MSG rats normalized adiposity. Our data indicate that adrenal exposure to the chronically high plasma leptin levels observed in MSG rats is involved in the loss of the inhibitory regulatory effect of leptin at the adrenal level, being therefore, at least in part, responsible for the increased total and free glucocorticoid peripheral levels found in adult MSG rats. Furthermore, this study strongly suggests that the adrenal over-function, frequently associated with different phenotypes of obesity, could be due to an adrenal resistance to the leptin negative regulation.