Centrally administered murine-leptin stimulates the hypothalamus-pituitary-adrenal axis through arginine-vasopressin

Starvation induces a decrease in circulating leptin levels a nd activation of the hypothalamus-pituitary-adrenal (HPA) axis. Leptin inhibits the HPA a xis in unfed rodents or genetically leptin-deficient ob/ob mice, whereas it stimulates corticotropin-releasing hormone (CRH) gene expression in the pa raventricular nucleus (PVN). However, the interactions between leptin, CRH and the HPA axis are poorly understood and are likely to be complex. We rec ently demonstrated that central leptin administration caused increases in p lasma arginine-vasopressin (AVP) and AVP gene expression of the PVN in nons tressful rats. AVP stimulates the release of adrenocorticotropic hormone (A CTH), but it also potentiates the action of CRH on ACTH release. In this st udy, we investigated the effects of leptin on plasma ACTH and corticosteron e levels, CRH rnRNA of the PVN and proopiomelanocortin (POMC) mRNA of the p ituitary in nonstrained rats. Intracerebroventricularly administered leptin caused increases in plasma ACTH and corticosterone levels in dose-dependen t manners. In Northern blot analyses, the leptin injection induced signific ant increases in the expression of CRH mRNA in the PVN and POMC mRNA in the pituitary. The increased plasma ACTH and corticosterone levels by leptin w ere attenuated with intracerebroventricular pretreatment of a V-1a receptor antagonist (OPC-21268) or a V-1a/V-1b receptor antagonist (dP[Tyr(Me)(2)]A VP), but not with that of a V-2 receptor antagonist (OPC-31260). The leptin -induced CRH mRNA expression in the PVN and POMC mRNA expression in the pit uitary were also reduced by the pretreatment with OPC-21268 and dP[Tyr(Me)( 2)]AVP. These results suggest that intracerebroventricular leptin administr ation activates the HPA axis by AVP receptor activation through V-1a recept ors in the PVN which in turn activates CRH neurons to drive ACTH and cortic osterone secretion in concert with AVP in nonstrained rats. Copyright (C) 2 000 S. Karger AG, Basel.