ORF01-03 - Central Melanocortin System Regulates Growth Hormone Secretion

The central melanocortin system plays a key role in regulating food intake, body weight, and glucose homeostasis. This system is composed of distinct neuronal populations, including neurons that express pro-opiomelanocortin (POMC), a prohormone that generates the alpha-melanocyte stimulating hormone (α-MSH), an agonist of melanocortin receptors (MCRs), or agouti-related protein (AgRP), an endogenous antagonist of MCRs. In the brain, α-MSH and AgRP act in neurons that express MC3-R and MC4-R. In addition to regulating metabolism, the melanocortin system also controls neuroendocrine neurons, thereby affecting the secretion of pituitary hormones. However, whether the melanocortin system also regulates growth hormone secretion remains unclear.
To address this question, we generated mice that constitutively express the hM3Dq-Gq receptor (CHRM3; DREADD technology) selectively in POMC neurons. Serial blood GH levels were collected before (-20, -10, and 0 minutes) and after (10, 20, 30, 40, 50, and 60 minutes) a systemic clozapine N-oxide (CNO) injection to evaluate the effects induced by activation of POMC-expressing cells. Activation of POMC neurons led to a significant increase in blood GH levels compared to baseline period or saline-injected mice. Next, to determine whether AgRP neurons inhibit GH secretion, mice carrying the hM3Dq-Gq receptor in both AgRP and GH-releasing hormone (GHRH)-expressing cells were produced. Thus, the effects of a simultaneous activation of GHRH and AgRP were compared to the response observed after GHRH activation only (control group). Our results demonstrate that co-activation of these neuronal populations attenuated GH secretion, compared to activation of GHRH neurons only. In addition, we observed that CNO-induced Fos expression in GHRH neurons was also attenuated by AgRP neuron activation.
Finally, to determine whether these effects are mediated by neurons expressing the melanocortin-4 receptor (MC4R), we used a model in which CHRM3 expression was restricted to MC4R-expressing cells. Activation of these neurons did not alter GH level, indicating that the observed effects are independent of MC4R-expressing cells.
In conclusion, our data demonstrated that the melanocortin system regulates GH secretion through direct actions on GHRH neurons in an MC4R-independent manner, revealing a novel central mechanism controlling GH secretion.