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 (alphaMSH) 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 alphaMSH (Act-alphaMSH) compared with that of N-desacetylated alphaMSH (Des-alphaMSH) is unclear, and regulation of acetylation by leptin has not been investigated. We show here that total hypothalamic alphaMSH levels are decreased in leptin-deficient ob/ob mice and increased in leptin-treated ob/ob and C57BL/6J mice. The increase in total alphaMSH occurred as soon as 3 h after leptin injection and was entirely due to an increase in Act-alphaMSH. 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-alphaMSH is far more potent than Des-alphaMSH in stimulating cAMP accumulation, an effect caused by a dramatically increased stability of Act-alphaMSH. Moreover, Des-alphaMSH 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-alphaMSH. Due to its increased stability, this posttranslational modification of alphaMSH may play a critical role in leptin action via the central melanocortin pathway.
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Authors | Li Guo, Heike Münzberg, Ronald C Stuart, Eduardo A Nillni, Christian Bjørbaek |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 101
Issue 32
Pg. 11797-802
(Aug 10 2004)
ISSN: 0027-8424 [Print] United States |
PMID | 15280541
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Leptin
- alpha-MSH
- Cyclic AMP
- Arylamine N-Acetyltransferase
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Topics |
- Acetylation
(drug effects)
- Animals
- Arylamine N-Acetyltransferase
(metabolism)
- Cyclic AMP
(metabolism)
- Enzyme Activation
(drug effects)
- Hypothalamus
(metabolism)
- Leptin
(deficiency, pharmacology)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neurons
(drug effects, enzymology)
- Protein Processing, Post-Translational
(drug effects)
- Rats
- Rats, Wistar
- alpha-MSH
(analysis, metabolism)
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