Melanocortins Mimic the Effects of Leptin to Restore Reproductive Function in Lean Hypogonadotropic Ewes

Abstract

Background/Aims: Leptin restores gonadotropic function in lean hypogonadotropic animals by an unknown mechanism. We aimed to test the hypothesis that restoration of gonadotropic function is a result of an upregulation of central acetylated melanocortin production. Methods and Results: Lean ovariectomised (OVX) ewes received intracerebroventricular (i.c.v.) infusions of leptin (or vehicle) for 3 days, which upregulated proopiomelanocortin (POMC) mRNA and restored pulsatile luteinizing hormone (LH) secretion. A melanocortin agonist (MTII), but not naloxone treatment, reinstated pulsatile LH secretion in lean OVX ewes. We treated (i.c.v.) lean OVX ewes with leptin (or vehicle) and measured peptide levels and post-translational modification in the arcuate nucleus (ARC). Levels of β-endorphin (β-END) were lower in lean animals, with no effect of leptin treatment. Desacetyl-α-MSH was the predominant form of α-melanocyte-stimulating hormone (α-MSH) in the ARC and levels were similar in all groups. In another group of lean and normal-weight OVX ewes, we measured the different forms of α-MSH in ARC, hypothalamus (ARC-removed) and the preoptic area (POA). Acetylated α-MSH levels were lower in lean animals in the terminal beds of the hypothalamus and POA but not the ARC. Conclusions: Leptin corrects the hypogonadotropic state in the lean condition by upregulation of POMC gene expression, and may increase transport and acetylation of melanocortins to target cells in the brain. Melanocortin treatment restores LH secretion in lean animals.

Gonadotropin-Inhibitory Hormone Is a Hypothalamic Peptide That Provides a Molecular Switch between Reproduction and Feeding

“…In this sense, we propose that GnIH may function as a molecular switch, between the two functions. This is consistent with the actions of a number of other peptides, which have opposing actions on reproduction and feeding, including NPY [40] and melanocortins [41], amongst others.…”

Influence of season and nutritional status on the direct effects of leptin, orexin-A and ghrelin on luteinizing hormone and growth hormone secretion in the ovine pituitary explant model

“…Investigations into the role of these peptides are confounded by the fact that most of these hormones and neuropeptides have both direct and indirect effects on the secretory function of the pituitary gland [4]. For example, recent studies have shown that leptin upregulates proopiomelanocortin gene expression and melanocortin production in the arcuate nucleus and Kiss1 messenger RNA (mRNA) levels in the preoptic area, leading indirectly to the restoration of LH secretion in lean ovariectomized ewes [26,27]. However, the identification of leptin receptor mRNA in 90% of gonadotrophs and 69% of somatotrophs in sheep is an indication of leptin activity and biological function in the pituitary gland [15], a phenomenon previously demonstrated by Zieba et al [11] and Amstalden et al [21] in bovine pituitary cells in vitro and postulated by McMahon et al [28] based on a study in calves.…”

New concepts of the central control of reproduction, integrating influence of stress, metabolic state, and season

“…This is consistent with the notion that adequate (or excessive) leptin levels are permissive of normal GnRH and/or LH secretion, whereas low leptin levels (in food-restricted, lean animals) signal energy deficiency. Leptin treatment of normal body weight OVX ewes reduces NPY gene expression, commensurate with reduction in food intake [128], but the same response is not seen in lean, foodrestricted OVX ewes [129], probably because there is were measured before treatment and at the end of treatment. Note that intracerebroventricular infusion of 4 mg/h leptin into food-restricted animals restored LH levels to normal in the food-restricted animals but had no effect in the animals on an ad lib diet.…”