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

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 -melanocytestimulating hormone ( 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 MSH (ActMSH) compared with that of N-desacetylated MSH (DesMSH) is unclear, and regulation of acetylation by leptin has not been investigated. We show here that total hypothalamic 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 MSH occurred as soon as 3 h after leptin injection and was entirely due to an increase in ActMSH. 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, ActMSH is far more potent than DesMSH in stimulating cAMP accumulation, an effect caused by a dramatically increased stability of ActMSH. Moreover, DesMSH 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 ActMSH. Due to its increased stability, this posttranslational modification of MSH may play a critical role in leptin action via the central melanocortin pathway.