Sexually Dimorphic Expression and Function of the Melanocortin-3 Receptor

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Neural systems regulating feeding behavior and reproduction communicate bidirectionally to gate reproductive events and to regulate energy stores for changes in reproductive states, such as pregnancy. The melanocortin-3 receptor (MC3R) is expressed in multiple nuclei that regulate reproduction and energy homeostasis such as the AgRP neurons of the arcuate nucleus, and exhibits a large sexual dimorphism in its level of expression in both humans and mice. Loss of the MC3R has particularly profound consequences for female animals. First, we demonstrate that MC3R is essential for fasting-induced suppression of the HPG axis in females. Second, we have identified fascinating sexual dimorphisms in feeding behavior in the absence of MC3R. For example, In the novelty suppressed feeding (NSF) assay in which fasted animals must enter an open field to retrieve food, MC3RKO males eat equivalent amounts to WT mice, while female MC3RKO fail to explore, and cease feeding entirely. In contrast, male but not female mice exhibit enhanced anorexia in response to restraint stress. AgRP neurons, the majority of which express MC3R, send information regarding nutritional state directly to reproductive and metabolic control centers, like the PVH and AVPV, and to behavioral control centers like the ventral tegmental area (VTA), paraventricular nucleus of the thalamus (PVT), and lateral parabrachial nucleus (PBl), and project indirectly to the insular cortex, involved in sensory interpretation of food cues and implicated in the pathophysiology of anorexia nervosa. This proposal will conduct the first systematic mapping and characterization of the MC3R neurons involved in the coordination of energy homeostasis, reproduction and feeding behavior, determine the mechanism(s) underlying the requirement of MC3R for fasting-induced suppression of the HPG axis, and identify the MC3R neurons and circuits mediating sexually dimorphic feeding behaviors.