Hypothalamic and hindbrain melanocortin receptors contribute to the feeding, thermogenic, and cardiovascular action of melanocortins.

Forebrain ventricular delivery of melanocortin receptor (MC3/4R) agonist increases energy expenditure and decreases food intake (FI). Because forebrain ventricular delivery provides ligand to various anatomically distributed MC3/4R-bearing nuclei, it is unclear which of the receptor subpopulations contributes to the feeding suppression and the sympathetic-thermogenic effects observed. The literature indicates that reexpression of MC4R in the paraventricular nucleus (PVH) affects the feeding but not the energetic phenotype of the MC4R knockout, suggesting that divergent MC4R populations mediate energy expenditure (hindbrain) and FI (hypothalamus) effects of stimulation. Not consistent with this view are data indicating that PVH sympathetic projection neurons express MC4Rs and that feeding effects are induced from hindbrain MC4R sites. Therefore, we hypothesize an opposing perspective: that stimulation of anatomically diverse MC3/4R-bearing nuclei triggers energetic as well as feeding effects. To test this hypothesis, ventricle subthreshold doses of MC3/4R agonist (5 and 10 pmol) were applied in separate experiments to six hindbrain and hypothalamic sites; core temperature (Tc), heart rate (HR), spontaneous activity (SPA), and FI were measured in behaving rats. Nucleus tractus solitarius and PVH stimulation increased Tc, HR, and SPA and decreased FI. Rostral ventrolateral medulla, parabrachial nucleus, and retrochiasmatic area stimulation increased Tc, HR, but not SPA, and decreased FI. The response profile differed to some extent for each nucleus tested, suggesting differential output circuitries for the measured parameters. Data are consistent with the view that energetic and feeding responses are not controlled by regionally divergent MC3/4Rs and can be elicited from multiple, anatomically distributed MC3/4R populations.