Peripheral administration of the N-terminal POMC fragment 1-28 to Pomc−/− mice reduces food intake and weight but does not affect adrenal growth or corticosterone production

摘要

Pro-opiomelanocortin (POMC) is a polypeptide precursor that undergoes extensive processing to yield a range of peptides with biologically diverse functions. POMC-derived ACTH is vital for normal adrenal function and the melanocortin α-MSH plays a key role in appetite control and energy homeostasis. However, the roles of peptide fragments derived from the highly conserved N-terminal region of POMC are less well characterised. We have used mice with a null mutation in the Pomc gene (Pomc^−/−) to determine the in vivo effects of synthetic N-terminal 1-28 POMC, which has been shown previously to possess adrenal mitogenic activity.1-28 POMC (20 μg) given subcutaneously for ten days had no effect on the adrenal cortex of Pomc^−/− mice with resultant cortical morphology and plasma corticosterone levels indistinguishable from sham treatment. Concurrent administration of 1-28 POMC and 1-24 ACTH (30μg per day) resulted in changes identical to 1-24 ACTH treatment alone, which consisted of upregulation of steroidogenic enzymes, elevation of corticosterone levels, hypertrophy of the zona fasciculata and regression of the X-zone.However, treatment of corticosterone-deplete Pomc^−/− mice with 1-28 POMC reduced cumulative food intake and total body weight. These anorexigenic effects were ameliorated when the peptide was administered to Pomc^−/− mice with circulating corticosterone restored either to a low physiological level by corticosterone-supplemented drinking water (CORT) or to a supraphysiological level by concurrent 1-24 ACTH administration. Further, icv administration of 1-28 POMC to CORT-treated Pomc^−/− mice had no effect on food intake or body weight. In wild type mice the effects of 1-28 POMC upon food intake and body weight were identical to sham but 1-28 POMC was able to ameliorate the hyperphagia induced by concurrent 1-24 ACTH treatment.In a mouse model which lacks all endogenous POMC peptides, subcutaneous treatment with synthetic 1-28 POMC alone can reduce food intake and body weight but has no impact upon adrenal growth or steroidogenesis.