28 Melanocortin 3 Receptor in Neural Circuits Linking Metabolic State with Reproduction and Growth

Abstract

Abstract Metabolic state must be communicated to the brain to regulate behavior, growth, nutrient partitioning and development to meet energetic demands. While it is clearly evident that reproduction and energy balance are closely intertwined, the neural circuits integrating these two processes are poorly understood. Recent functional data suggests the melanocortin 3 receptor (MC3R) mediates the exchange of information between reproductive and metabolic state. Additionally, females exhibit uniquely aberrant metabolic and reproductive phenotypes after deletion of MC3R. In this work, we aimed to characterize the role of MC3R neural circuits in linking metabolic state with reproduction and growth in females. We found that MC3R is expressed in brain regions known to have a role in the control of reproductive and metabolic state, including the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARH). In the ARH of female mice, significant differences in overall levels of Mc3r mRNA were not observed at postnatal day 16 (P16), P28 or P48, nor did the percentage of ARH Kiss1, Esr1, Sst, Pomc or Agrp neurons doubly-labeled for Mc3r appear to change during postnatal development. However, the percentage of ARH Ghrh neurons labeled for Mc3r significantly increased from P16 to P48. Thus, MC3R in the ARH may play a potential role in conveying metabolic signals critical for growth during development. In the AVPV of female mice, overall abundance of Mc3r mRNA was low at P16, but increased significantly by P28, and was further elevated in mature mice (P48). Additionally, the percentage of Kiss1- and Esr1-expressing neurons in the AVPV labeled for Mc3r increased significantly between P16 and P48, suggesting that Mc3r may have an important role in the timing of sexual maturation. In addition to the direct regulatory action of MC3R expressed in KISS1 neurons in the AVPV, the impact of MC3R signaling may also be transmitted transynaptically via direct neural projections from MC3R neurons to KISS1 neurons in the AVPV, or to GnRH neurons in the rostral preoptic area. Clearly labeled MC3R terminals were observed in close apposition to both KISS1 neurons in the AVPV, and GnRH neurons in the rostral medial preoptic area. Although both the GnRH and KISS1 neuronal populations appeared heavily innervated by MC3R neurons, the density of MC3R terminals onto KISS1 neurons appeared to be substantially greater than that onto GnRH neurons, suggesting that inputs to AVPV neurons may be particularly impactful on reproduction. Thus, MC3R may not only regulate the activity of KISS1 neurons in the AVPV directly, but may also function transynaptically as an important neurobiological substrate for coordination of metabolic state with sexual maturation and reproductive function.