The central melanocortin system regulates growth hormone secretion

The central melanocortin system is crucial for controlling food intake and metabolism. It includes neurons that produce pro-opiomelanocortin (POMC), a prohormone that generates the melanocortin receptor (MCR) agonist alpha-melanocyte-stimulating hormone (α-MSH), and neurons that produce agouti-related protein (AgRP), an endogenous MCR antagonist. This system also influences neuroendocrine neurons, thereby impacting pituitary hormone secretion. However, it remains unclear whether the central melanocortin system also modulates growth hormone (GH) secretion. Here we showed that arcuate nucleus (ARH) GH-releasing hormone (GHRH) neurons receive inputs from α-MSH and AgRP axons. α-MSH activates a subset (∼25%) of ARH GHRH neurons. Serial blood GH measurements were taken before and after systemic saline or clozapine N-oxide injections in mice expressing the excitatory hM3Dq-Gq receptor in POMC-expressing cells. Activation of POMC-expressing cells elevated blood GH levels compared with baseline or saline-injected mice, in both males and females. To determine whether AgRP neurons inhibit GH secretion, mice expressing the hM3Dq-Gq receptor simultaneously in AgRP- and GHRH-expressing cells were created. While chemogenetic activation of GHRH neurons caused a strong GH secretion, co-activation of AgRP neurons inhibited this response in both sexes. Additionally, Fos expression in GHRH-activated neurons was blunted when AgRP neurons were co-stimulated. Mice expressing the hM3Dq-Gq receptor only in MC4R-expressing cells were also investigated; however, activation of MC4R neurons did not alter GH levels. In conclusion, the central melanocortin system modulates the activity of GHRH neurons and GH secretion possibly through MC4R-independent pathways. These findings highlight a critical hypothalamic neurocircuit that integrates metabolic cues to regulate the somatotropic axis. Significance Statement The central melanocortin system processes both short- and long-term nutritional signals to regulate metabolism and various neuroendocrine axes. Here, we show that growth hormone (GH) secretion is controlled by hypothalamic neurons of the central melanocortin system, including populations that express POMC and AgRP. This regulation occurs, at least in part, through modulation of GH-releasing hormone neuron activity, a key group of cells that control pituitary GH secretion. Overall, these findings reveal a hypothalamic circuit that links nutritional status to the regulation of the GH axis, providing new insights into how growth is adaptively controlled by energy availability.