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Background: Obesity and type 2 diabetes are strongly associated pathologies, currently considered as a worldwide epidemic problem. Understanding the mechanisms that drive the development of these diseases would enable to develop new therapeutic strategies for their prevention and treatment. Particularly, the role of the brain in the energy and glucose homeostasis has been studied for two decades. In specific, the hypothalamus contains well-identified neural networks regulating appetite and potentially also glucose homeostasis. A new concept has thus emerged, suggesting that obesity and diabetes could be due to a dysfunction of the same, still poorly understood, neural networks. Summary: The neuropeptide 26RFa (also termed QRFP) belongs to the family of RFamide regulatory peptides and has been identified as the endogenous ligand of the human G protein-coupled receptor GPR103 (QRFPR). The primary structure of 26RFa is strongly conserved during vertebrate evolution, suggesting its crucial roles in the control of vital functions. Indeed, the 26RFa/GPR103 peptidergic system is reported to be involved in the control of various neuroendocrine functions, notably the control of energy metabolism in which it plays an important role, both centrally and peripherally, since 26RFa regulates feeding behavior, thermogenesis and lipogenesis. Moreover, 26RFa is reported to control glucose homeostasis both peripherally, where it acts as an incretin, and centrally, where the 26RFa/GPR103 system relays insulin signaling in the brain to control glucose metabolism. Key Messages: This review gives a comprehensive overview of the role of the 26RFa/GPR103 system as a key player in the control of energy and glucose metabolism. In pathophysiological context, this neuropeptidergic system represents a prime therapeutic target whose mechanisms are highly relevant to decipher.

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