Acetylation of α-MSH Involved in Regulating Food Intake

Abstract

One of the pathways by which leptin inhibits food intake is by stimulating the proopiomelanocortin (POMC) neurons, which produce α-melanocyte-stimulating hormone (α-MSH), a POMC-derived bioactive peptide. Guo et al. show that the hypothalamus of mice and rats contains desacetylated α-MSH (Des-α-MSH) and acetylated α-MSH (Act-α-MSH) and that the abundance of Act-α-MSH is stimulated by injection of the wild-type or leptin-deficient ob/ob mice with leptin. Biochemical analysis of hypothalamic protein extracts from leptin-treated or untreated mice showed that leptin produced an increase in conversion of exogenously added Des-α-MSH to Act-α-MSH, which suggests that leptin stimulates the activity of an N -acetyltransferase in the hypothalamus. It was known and reproduced by Guo et al. that Act-α-MSH was more potent than Des-α-MSH in inhibiting food intake in rats. However, Guo et al. demonstrate using a transfected cell system in the absence of phosphodiesterase inhibitors [conditions used previously to assay for the ability of Act-α-MSH and Des-α-MSH to stimulate the melanocortin 4 receptor (MC4R) included such an inhibitor and showed no difference in the two ligands' activity] that Act-α-MSH is more potent at stimulating the production of cAMP (adenosine 3′,5′ monophosphate). The difference in the activities of the two ligands may lie in their relative stability. Indeed, both when injected into mice or rat brains and when added to the medium in the presence of cultured cells, Des-α-MSH was rapidly undetectable, presumably due to degradation, whereas Act-α-MSH was more persistent. Thus, posttranslational processing of α-MSH by a leptin-stimulated hypothalamic N -acetyltransferase results in the production of the stable Act-α-MSH, which participates in downstream signals controlling food intake. L. Guo, H. Münzberg, R. C. Stuart, E. A. Nillni, C. Bjørbæk, N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin. Proc. Natl. Acad. Sci. U.S.A . 101 , 11797-11802 (2004). [Abstract] [Full Text]