Effects of leptin and melanocortin signaling interactions on pubertal development and reproduction - PubMed (original) (raw)

Effects of leptin and melanocortin signaling interactions on pubertal development and reproduction

Davelene D Israel et al. Endocrinology. 2012 May.

Abstract

Leptin and melanocortin signaling control ingestive behavior, energy balance, and substrate utilization, but only leptin signaling defects cause hypothalamic hypogonadism and infertility. Although GnRH neurons do not express leptin receptors, leptin influences GnRH 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 agouti-related 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 GnRH neurons, providing further evidence that melanocortin signaling influences GnRH neuron activity. These studies thus establish melanocortin signaling as an important component in the leptin-mediated regulation of GnRH neuron activity, initiation of puberty and fertility.

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Figures

Fig. 1.

Fig. 1.

Impact of alterations of melanocortinergic tone on metabolic characteristics of db/db mice.

Fig. 2.

Fig. 2.

Mutations of Lepr, Agrp and Mc4r do not alter follicular development.

Fig. 3.

Fig. 3.

Restoration of mammary gland development and milk production in db/db females by mutations of Agrp and Mc4r.

Fig. 4.

Fig. 4.

Melanocortins regulate GnRH neurons via MC4R.

Fig. 5.

Fig. 5.

Modeling of a network whereby leptin sensitive melanocortinergic neurons (both AGRP/NPY neurons and POMC neurons) directly regulate GnRH neuron activity via MC4R.

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