Abstract
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.
Highlights
The neuropeptide 26RFa, referred to as QRFP, is the latest member of the RFamide peptide family discovered [5, 9, 16]. 26RFa and its N-extended form 43RFa were identified as the cognate ligands of the human orphan G-protein-coupled receptor, GPR103 [6, 9, 16, 30]
26RFa stimulates food intake [5, 20, 21, 30], and the neuropeptide exerts its orexigenic activity via a modulation of the neuropeptide Y (NPY)/ POMC network in the arcuate nucleus [20]
The expression of prepro26RFa mRNA is upregulated in the hypothalamus of genetically obese ob/ob and db/db mice and rodents submitted to an HF diet [27, 30]
Summary
The neuropeptide 26RFa, referred to as QRFP (for pyroglutamilated RFamide peptide), is the latest member of the RFamide peptide family discovered [5, 9, 16]. 26RFa and its N-extended form 43RFa were identified as the cognate ligands of the human orphan G-protein-coupled receptor, GPR103 [6, 9, 16, 30]. These observations have been recently confirmed by data obtained from 26RFadeficient mice showing that the knockout (KO) mice are lean and hypophagic and that, under a high-fat (HF) diet, the 26RFa KO mice show a lower weight gain than the wild-type animals [22]. The expression of prepro26RFa mRNA is upregulated in the hypothalamus of genetically obese ob/ob and db/db mice and rodents submitted to an HF diet [27, 30] These findings support the notion that 26RFa could play a role in the development and maintenance of the obese status [7]
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