No abstract

This mini-review deals with the neuropeptide 26RFa (or QRFP) which is a member of the RFamide peptide family discovered simultaneously by three groups in 2003. 26RFa (or its N-extended form 43RFa) was subsequently shown to be the endogenous ligand of the human orphan receptor GPR103. In the brain, 26RFa and GPR103mRNA are primarily expressed in hypothalamic nuclei involved in the control of feeding behavior, and at the periphery, the neuropeptide and its receptor are present in abundance in the gut and the pancreatic islets, suggesting that 26RFa is involved in the regulation of energy metabolism. Indeed, 26RFa stimulates food intake when injected centrally, and its orexigenic effect is even more pronounced in obese animals. The expression of 26RFa is up-regulated in the hypothalamus of obese animals, supporting that the 26RFa/GPR103 system may play a role in the development and/or maintenance of the obese status. Recent data indicate that 26RFa is also involved in the regulation of glucose homeostasis. 26RFa reduces glucose-induced hyperglycemia, increases insulin sensitivity and insulinemia. Furthermore, an oral ingestion of glucose strongly stimulates 26RFa release by the gut, indicating that 26RFa is a novel incretin. Finally, 26RFa is able to prevent pancreatic β cell death and apoptosis. This brief overview reveals that 26RFa is a key neuropeptide in the regulation of energy metabolism. Further fields of research are suggested including the pathophysiological implication of the 26RFa/GPR103 system.

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.