The Orexigenic Activity of the Hypothalamic Neuropeptide 26RFa Is Mediated by the Neuropeptide Y and Proopiomelanocortin Neurons of the Arcuate Nucleus

Abstract

26RFa is a hypothalamic RFamide neuropeptide that was identified as the endogenous ligand of the orphan G protein-coupled receptor, GPR103, and that stimulates appetite in mice. Up until now, the mechanism of action of 26RFa in the hypothalamic control of food intake remains unknown. The high density of GPR103 in the arcuate nucleus (Arc) prompted us to investigate, in the present study, the effects of 26RFa on the rat neuropeptide Y (NPY)/proopiomelanocortin (POMC) system. Intracerebroventricular injection of 26RFa stimulated NPY expression and release in the basal hypothalamus, whereas it decreased POMC expression and alpha-MSH release, and these effects were associated with an increase in food intake. A double in situ hybridization procedure indicated that the 26RFa receptor is present in NPY neurons of the Arc, but not in POMC neurons. Central administration of NPY Y1 and Y5 receptor antagonists abolished the inhibitory effects of 26RFa on POMC expression and alpha-MSH release, and reversed 26RFa-induced food consumption. Finally, 26RFa antagonized the effects of leptin on NPY expression and release, POMC expression and alpha-MSH release, and food intake. Altogether, the present data demonstrate for the first time that 26RFa exerts its orexigenic activity by stimulating the release of NPY in the Arc, which in turn inhibits POMC neurons by activating the Y1 and Y5 receptors. It is also suggested that the balance 26RFa/leptin is an important parameter in the maintenance of energy homeostasis.

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

“…This sequence similarity and lack of identity suggests that QRFP receptors diverged from orexin receptors earlier than NPFF receptors but experienced selective pressure to retain homologous sequence. Reported responses to central administration of QRF peptides, the ligands for QRFP receptor, include increases in arousal and locomotor activity, increased feeding, energy balance regulation, and the modulation of pain responses (Thuau et al, 2005;Moriya et al, 2006;Takayasu et al, 2006;Yamamoto et al, 2008;Lectez et al, 2009;Yamamoto et al, 2009), functions remarkably similar to that of orexin.…”

Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis

“…Neuroanatomical observations revealed that 26RFa-and GPR103-expressing neurons are primarily localized in hypothalamic nuclei involved in the control of feeding behavior (1,2,5,7). Indeed, intracerebroventricular administration of 26RFa or 43RFa stimulates food intake (1,5,8,9), and the neuropeptide exerts its orexigenic activity by modulating the neuropeptide Y/proopiomelanocortin system in the arcuate nucleus (9). Chronic injection of 43RFa induces a significant increase in mice body weight and fat mass, which is associated with a hyperphagic behavior (8), and the orexigenic activities of 26RFa and 43RFa are more robust in rodents fed a high-fat diet (8,10).…”

RFamide Peptides 43RFa and 26RFa Both Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets but Exert Opposite Effects on Insulin Secretion

“…In humans and rodents, 43RFa, 26RFa, and GPR103 are mainly expressed in brain, particularly in the hypothalamus (8), as well as in peripheral tissues, including the eye, testis, thyroid, adipose tissue, and macrophages (6,(9)(10)(11). 43RFa and 26RFa have been implicated in many physiological functions, including stimulation of food intake (5,(12)(13)(14)(15)(16)(17), regulation of gonadotropic axis (18,19), aldosterone secretion (7,20), bone formation (21), adipogenesis and inflammation (10,11), blood pressure (12), and prostate cancer differentiation and migration (22).…”