| First Author | Guo L | Year | 2004 |
| Journal | Proc Natl Acad Sci U S A | Volume | 101 |
| Issue | 32 | Pages | 11797-802 |
| PubMed ID | 15280541 | Mgi Jnum | J:91785 |
| Mgi Id | MGI:3050737 | Doi | 10.1073/pnas.0403165101 |
| Citation | Guo L, et al. (2004) N-acetylation of hypothalamic alpha-melanocyte-stimulating hormone and regulation by leptin. Proc Natl Acad Sci U S A 101(32):11797-802 |
| abstractText | 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. |
