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N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin

PNAS, 10 August 2004
Vol. 101, Issue 32, p. 11797-11802
DOI: 10.1073/pnas.0403165101

N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin

  1. Li Guo *,
  2. Heike Münzberg *,
  3. Ronald C. Stuart ,
  4. Eduardo A. Nillni , and
  5. Christian Bjørbæk * ,
  1. *Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; and Division of Endocrinology, Rhode Island Hospital and Brown Medical School, Providence, RI 02903
  1. Edited by Donald F. Steiner, University of Chicago, Chicago, IL, and approved June 25, 2004 (received for review 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 α-melanocyte-stimulating hormone (αMSH) 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 αMSH (Act-αMSH) compared with that of N-desacetylated αMSH (Des-αMSH) is unclear, and regulation of acetylation by leptin has not been investigated. We show here that total hypothalamic αMSH levels are decreased in leptin-deficient ob/ob mice and increased in leptin-treated ob/ob and C57BL/6J mice. The increase in total αMSH occurred as soon as 3 h after leptin injection and was entirely due to an increase in Act-αMSH. 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-αMSH is far more potent than Des-αMSH in stimulating cAMP accumulation, an effect caused by a dramatically increased stability of Act-αMSH. Moreover, Des-αMSH 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-αMSH. Due to its increased stability, this posttranslational modification of αMSH may play a critical role in leptin action via the central melanocortin pathway.

Footnotes

  • 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}bidmc.harvard.edu.

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

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

Citation:

L. Guo, H. Münzberg, R. C. Stuart, E. A. Nillni, and C. Bjørbæk, N-acetylation of hypothalamic α-melanocyte-stimulating hormone and regulation by leptin. PNAS 101, 11797-11802 (2004).

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