Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 101 (32): 11797-11802

Copyright © 2004 by the National Academy of Sciences.

MEDICAL 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}bidmc.harvard.edu.

© 2004 by The National Academy of Sciences of the USA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Ghrelin affects the hypothalamus-pituitary-thyroid axis in humans by increasing free thyroxine and decreasing TSH in plasma.
M. Kluge, S. Riedl, M. Uhr, D. Schmidt, X. Zhang, A. Yassouridis, and A. Steiger (2010)
Eur. J. Endocrinol. 162, 1059-1065
   Abstract »    Full Text »    PDF »
Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax).
E. Sanchez, V. C. Rubio, D. Thompson, J. Metz, G. Flik, G. L. Millhauser, and J. M. Cerda-Reverter (2009)
Am J Physiol Regulatory Integrative Comp Physiol 296, R1293-R1306
   Abstract »    Full Text »    PDF »
Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin.
E. A. Nillni (2007)
Endocrinology 148, 4191-4200
   Abstract »    Full Text »    PDF »
Differential effects of fasting and leptin on proopiomelanocortin peptides in the arcuate nucleus and in the nucleus of the solitary tract.
M. Perello, R. C. Stuart, and E. A. Nillni (2007)
Am J Physiol Endocrinol Metab 292, E1348-E1357
   Abstract »    Full Text »    PDF »
A Comparative Study of the Central Effects of Specific Proopiomelancortin (POMC)-Derived Melanocortin Peptides on Food Intake and Body Weight in Pomc Null Mice.
Y. C. L. Tung, S. J. Piper, D. Yeung, S. O'Rahilly, and A. P. Coll (2006)
Endocrinology 147, 5940-5947
   Abstract »    Full Text »    PDF »
Peripherally administered desacetyl {alpha}-MSH and {alpha}-MSH both influence postnatal rat growth and associated rat hypothalamic protein expression.
C.-S. J. Wu, D. R. Greenwood, J. M. Cooney, D. J. Jensen, M. A. Tatnell, G. J. S. Cooper, and K. G. Mountjoy (2006)
Am J Physiol Endocrinol Metab 291, E1372-E1380
   Abstract »    Full Text »    PDF »
The Role of Intracerebroventricular Administration of Leptin in the Stimulation of Prothyrotropin Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus.
M. Perello, R. C. Stuart, and E. A. Nillni (2006)
Endocrinology 147, 3296-3306
   Abstract »    Full Text »    PDF »
Divergent Regulation of Proopiomelanocortin Neurons by Leptin in the Nucleus of the Solitary Tract and in the Arcuate Hypothalamic Nucleus.
L. Huo, H. J. Grill, and C. Bjorbaek (2006)
Diabetes 55, 567-573
   Abstract »    Full Text »    PDF »
BIOMEDICINE: Separation of Conjoined Hormones Yields Appetite Rivals.
R. Nogueiras and M. Tschop (2005)
Science 310, 985-986
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882