Physiological Roles of Gonadotropin-Inhibitory Hormone Signaling in the Control of Mammalian Reproductive Axis: Studies in the NPFF1 Receptor Null Mouse

Author:

León Silvia1,García-Galiano David1,Ruiz-Pino Francisco1,Barroso Alexia1,Manfredi-Lozano María1,Romero-Ruiz Antonio1,Roa Juan1,Vázquez María J.1,Gaytan Francisco1,Blomenrohr Marion1,van Duin Marcel1,Pinilla Leonor1,Tena-Sempere Manuel1

Affiliation:

1. Department of Cell Biology, Physiology and Immunology, University of Córdoba; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III; and Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofia, 14004 Córdoba, Spain

Abstract

RF-amide-related peptide-3 (RFRP-3), the mammalian ortholog of the avian gonadotropin-inhibiting hormone (GnIH), operates via the NPFF1 receptor (NPFF1R) to repress the reproductive axis, therefore acting as counterpart of the excitatory RF-amide peptide, kisspeptin (ligand of Gpr54). In addition, RFRP-3 modulates feeding and might contribute to the integrative control of energy homeostasis and reproduction. Yet, the experimental evidence supporting these putative functions is mostly indirect, and the physiological roles of RFRP-3 remain debatable and obscured by the lack of proper analytical tools and models. To circumvent these limitations, we characterize herein the first mouse line with constitutive inactivation of NPFF1R. Ablation of NPFF1R did not compromise fertility; rather, litters from NPFF1R null mice were larger than those from wild-type animals. Pubertal timing was not altered in NPFF1R deficient mice; yet, pre-pubertal knockout (KO) males displayed elevated LH levels, which normalized after puberty. Adult NPFF1R null male mice showed increased Kiss1 expression in the hypothalamic arcuate nucleus, higher serum FSH levels, and enhanced LH responses to GnRH. However, genetic elimination of NPFF1R was unable to reverse the state of hypogonadism caused by the lack of kisspeptin signaling, as revealed by double NPFF1R/Gpr54 KO mice. NPFF1R null mice displayed altered feedback responses to gonadal hormone withdrawal. In addition, metabolic challenges causing gonadotropin suppression, such as short-term fasting and high-fat diet, were less effective in dampening LH secretion in NPFF1R-deficient male mice, suggesting that absence of this inhibitory pathway partially prevented gonadotropin suppression by metabolic stress. Our data are the first to document the impact of elimination of GnIH signaling on reproductive parameters and their modulation by metabolic challenges. Whereas, in keeping with its inhibitory role, the NPFF1R pathway seems dispensable for preserved puberty and fertility, our results surface different alterations due to the lack of GnIH signaling that prominently include changes in the sensitivity to fasting- and obesity-associated hypogonadotropism.

Publisher

The Endocrine Society

Subject

Endocrinology

Reference39 articles.

1. 2006 Physiology of the gonadotropin-releasing hormone neuronal network;Herbison

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4. A novel avian hypothalamic peptide inhibiting gonadotropin release;Tsutsui;Biochem Biophys Res Commun,2000

5. Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals;Kriegsfeld;Proc Natl Acad Sci USA,2006

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