Central regulation of energy homeostasis and the reproductive axis

Abstract

Alarin is a recently discovered splice variant of the galanin-like peptide (GALP) gene. Alarin is a highly conserved 25 amino acid peptide which shares its first 5 amino acids with GALP, but lacks the galanin receptor binding domain, suggesting that it mediates its biological effects through alternative receptors. Alarin has been detected in the rodent hypothalamus. GALP has a well-characterised role in the integration of energy and reproductive homeostasis. Intracerebroventricular (ICV) alarin increases food intake and plasma luteinising hormone (LH) levels in rats. Alarin stimulates the release of the orexigenic neuropeptide Y (NPY) and gonadotrophin releasing hormone (GnRH) from hypothalamic explants, and GnRH release from an immortalised GnRH releasing cell line. Pre-treatment with a GnRH antagonist blocked the alarin-induced increase in plasma LH levels in vivo. These results suggest that ICV alarin activates the HPG axis via hypothalamic GnRH release. My data also suggests that alarin does not bind to the known galanin receptors. The ventral tegmental area (VTA) is the origin of the mesolimbic dopamine pathway, which mediates the rewarding properties of palatable food. Recent work suggests that the VTA reward pathway is regulated by appetite-regulating signals including leptin and ghrelin. I have shown that intra-VTA melanocortin receptor agonist administration inhibits food intake and administration of an antagonist stimulates food intake in rats, suggesting that the melanocortin system may be involved in hedonic regulation of appetite, in addition to its role in homeostatic regulation of appetite. These studies have elucidated the biological effects of alarin in the regulation of appetite and the HPG axis, and identified a role for the melanocortin system in regulating the central reward circuitry modulating food intake. Further work is required to determine the receptor by which alarin mediates its effect and its precise physiological function, and the physiological importance of the VTA melanocortin system.