Leptin and melanocortin signaling control ingestive behavior, energy balance, and substrate utilization, but only leptin signaling defects cause hypothalamic hypogonadism and infertility. Although Gn RH neurons do not express leptin receptors, leptin influences Gn RH neuron activity via regulation of immediate downstream mediators including the neuropeptides neuropeptide Y and the melanocortin agonist and antagonist, α-MSH, agouti-related peptide, respectively. Here we show that modulation of melanocortin signaling in female db/db mice through ablation of agoutirelated peptide, or heterozygosity of melanocortin 4 receptor, restores the timing of pubertal onset, fertility, and lactation. Additionally, melanocortin 4 receptor activation increases action potential firing and induces c-Fos expression in Gn RH neurons, providing further evidence that melanocortin signaling influences Gn RH neuron activity. These studies thus establish melanocortin signaling as an important component in the leptin-mediated regulation of Gn RH neuron activity, initiation of puberty and fertility.
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