RFRP-3, the Mammalian Ortholog of GnIH, Is a Novel Modulator Involved in Food Intake and Glucose Homeostasis

Abstract

RF amide-related peptide 3 (RFRP-3) is a reproductive inhibitor and an endogenous orexigenic neuropeptide that may be involved in energy homeostasis. In this study, we evaluated the effect of acute or chronic RFRP-3 treatment (administered via intraperitoneal injection) on the food intake, meal microstructure and weight of rats, as well as the mechanism through which RFRP-3 is involved in glucose metabolism in the pancreas and glucose disposal tissues of rat in vivo. Our results showed that the intraperitoneal administration of RFRP-3 to rats resulted in marked body mass increased, hyperphagia, hyperlipidemia, hyperglycemia, glucose intolerance, hypoinsulinism, hyperglucagon, and insulin resistance, as well as significant increases in the size of pancreatic islets and the inflammatory reaction. Thus, we strongly assert that RFRP-3 as a novel neuroendocrine regulator involved in blood glucose homeostasis.

Effects of Chronic Intracerebroventricular Infusion of RFamide-Related Peptide-3 on Energy Metabolism in Male Mice

“…injection of GnIH/RFRP-3 increased food intake in chicks [ 34 , 35 ], mice [ 40 ], rats [ 25 , 28 ], sheep [ 40 ], and cynomolgus monkeys [ 40 ]. In addition, a recent study showed that chronic intraperitoneal injection of RFRP-3 to rats stimulated feeding behavior and regulated blood glucose homeostasis [ 36 ]. However, the chronic central effects of RFRP-3 have not been elucidated in any animals.…”

“…These results suggest that body mass may be independent of food intake and may be related to the decrease in energy expenditure. It has been recently reported that intraperitoneally injected RFRP-3 slightly increased body mass and serum lipid levels in rats [ 36 ]. Although the serum glucose level was increased by the infusion of RFRP-3 in this study, no change in the serum lipid and insulin levels was found ( Table 1 ).…”

“…injection of GnIH/RFRP-3 in chickens and rats [ 25 , 28 , 34 , 35 ]. In addition, a recent study showed that chronic intraperitoneal injection of RFRP-3 had an orexigenic effect and regulated glucose homeostasis in rats [ 36 ]. Therefore, it is possible that RFRP not only influences reproductive functions, but may also regulate energy homeostasis in birds and mammals.…”

Gonadotropin Inhibitory Hormone and Its Receptor: Potential Key to the Integration and Coordination of Metabolic Status and Reproduction

“…This has further been confirmed in rats, as well as chickens, with insufficient fat stores resulting in pubertal delay ( 136 , 149 , 150 ) and diet-induced obesity resulting in declined reproductive capacity ( 151 , 152 ). In a recent study, GnIH injections resulted in the elevation of serum total triglycerides and cholesterol ( 153 ), leading to increased uptake of triglycerides by the adipose tissue ( 142 ). Thus, it could be hypothesized that GnIH acts to control fat deposition in adipose tissue not only in immature animals but also in adults.…”

Role of central kisspeptin and RFRP‐3 in energy metabolism in the male Wistar rat

“…Regarding glucose metabolism, little is known about possible effects of RFRP‐3. Intraperitoneal administration of RFRP‐3 has been shown to change circulating glucose concentrations, as well as insulin receptor and glucose transporter expression in testis and adipose tissue, 13,56 and a lack of the RFRP‐3 receptor in NPFF1R KO mice worsened the metabolic impact of a high‐fat diet on glucose homeostasis in male but not female mice 6 . RFRP‐3 neurones also project to the NPY‐ and POMC‐containing neurones in the ARC 57 ; thus, in view of the reported opposite effects on POMC neuronal activity, 42 the comparable effects on glucose metabolism may appear unexpected.…”