👤 Francesca Copperi

The melanocortin receptor 4 (MC4R) plays a key role in the CNS regulation of metabolism. In addition to its role within the hypothalamus, other brain areas, including the dorsal raphe nucleus (DRN), express MC4R. However, the identity and role of these neurons in metabolism regulation are not fully understood. We performed studies to address these questions. We generated Mc4r-cre;Vgat-FlpO and Mc4r-cre;Vglut2-FlpO mice to determine the contribution of these MC4R neuronal populations in DRN. We then chemogenetically activated or inhibited the GABAergic and glutamatergic populations of MC4R. Finally, we selectively deleted MC4R from these two neuronal populations and studied the impact on whole-body metabolism. We found that about 60% of DRN MC4R neurons are GABAergic (Vgat), while only about 20% are glutamatergic (Vglut2). Most of the projections onto DRN neurons originated from the arcuate nucleus (ARC)-POMC neurons, and only a small input from the nucleus of the solitary tract (NTS)-POMC neurons was identified. Significant projections of DRN MC4R/Vgat neurons were observed in the paraventricular nucleus of the hypothalamus (PVN). Chemogenetic activation or inhibition of MC4R/Vgat neurons increased or inhibited food intake, respectively. No effects were observed when the same approach was used in MC4R/Vglut2 neurons. Furthermore, only chemogenetic manipulation of the MC4R/Vgat neurons affected anxiety-like behavior, which was associated with changes in serotonin staining in the DRN. Finally, MC4R-selective deletion in Vgat but not Vglut2 neurons affected whole-body metabolism. These findings suggest that DRN MC4R/Vgat neurons receiving projections from the ARC POMC neurons and projecting to the hypothalamic PVN play a role in metabolism regulation. In addition, this same DRN neuronal subpopulation affects anxiety-like behavior by modulating DRN serotonin neurons. Show less

Increasing evidence indicates that the melanocortin system is not only a central player in energy homeostasis, food intake and glucose level regulation, but also in the modulation of cardiovascular functions, such as blood pressure and heart rate. The melanocortins, and in particular α- and γ-MSH, have been shown to exert their cardiovascular activity both at the central nervous system level and in the periphery (e.g., in the adrenal gland), binding their receptors MC3R and MC4R and influencing the activity of the sympathetic nervous system. In addition, some studies have shown that the activation of MC3R and MC4R by their endogenous ligands is able to improve the outcome of cardiovascular diseases, such as myocardial and cerebral ischemia. In this brief review, we will discuss the current knowledge of how the melanocortin system influences essential cardiovascular functions, such as blood pressure and heart rate, and its protective role in ischemic events, with a particular focus on the central regulation of such mechanisms. Show less