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PNAS 101 (32): 11797-11802

Copyright © 2004 by the National Academy of Sciences.


N-acetylation of hypothalamic {alpha}-melanocyte-stimulating hormone and regulation by leptin

Li Guo *, Heike Münzberg *, Ronald C. Stuart {dagger}, Eduardo A. Nillni {dagger}, and Christian Bjørbæk *, {ddagger}

*Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; and {dagger}Division of Endocrinology, Rhode Island Hospital and Brown Medical School, Providence, RI 02903

Edited by Donald F. Steiner, University of Chicago, Chicago, IL, and approved June 25, 2004

Received for publication May 5, 2004.

Abstract: The central melanocortin system is critical in the regulation of appetite and body weight, and leptin exerts its anorexigenic actions partly by increasing hypothalamic proopiomelanocortin (POMC) expression. The POMC-derived peptide {alpha}-melanocyte-stimulating hormone ({alpha}MSH) is a melanocortin 4 receptor agonist, and its potency in reducing energy intake is strongly increased by N-acetylation. The reason for the higher biological activity of N-acetylated {alpha}MSH (Act-{alpha}MSH) compared with that of N-desacetylated {alpha}MSH (Des-{alpha}MSH) is unclear, and regulation of acetylation by leptin has not been investigated. We show here that total hypothalamic {alpha}MSH levels are decreased in leptin-deficient ob/ob mice and increased in leptin-treated ob/ob and C57BL/6J mice. The increase in total {alpha}MSH occurred as soon as 3 h after leptin injection and was entirely due to an increase in Act-{alpha}MSH. Consistent with this observation, leptin rapidly induced the enzymatic activity of a N-acetyltransferase in the hypothalamus of mice. In 293T cells expressing the melanocortin 4 receptor, Act-{alpha}MSH is far more potent than Des-{alpha}MSH in stimulating cAMP accumulation, an effect caused by a dramatically increased stability of Act-{alpha}MSH. Moreover, Des-{alpha}MSH is rapidly degraded in the hypothalamus after intracerebroventricular injection in rats and was less potent in inhibiting energy intake. The results suggest that leptin activates a N-acetyltransferase in POMC neurons, leading to increased hypothalamic levels of Act-{alpha}MSH. Due to its increased stability, this posttranslational modification of {alpha}MSH may play a critical role in leptin action via the central melanocortin pathway.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: POMC, proopiomelanocortin; {alpha}MSH, {alpha}-melanocyte-stimulating hormone; MC4R, melanocortin 4 receptor; Act-{alpha}MSH, N-acetylated {alpha}MSH; Des-{alpha}MSH, desacetylated {alpha}MSH; IBMX, 3-isobutyl-1-methylxanthine; PC, prohormone convertase.

{ddagger} To whom correspondence should be addressed at: Division of Endocrinology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: cbjorbae{at}

© 2004 by The National Academy of Sciences of the USA

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