Acute but not chronic central administration of the neuropeptide 26RFa (QRFP) improves glucose homeostasis in obese/diabetic mice

International audienceIntroduction: The aim of the study is to investigate whether acute or chronic central administration of the hypothalamic neuropeptide 26RFa may ameliorate the glycemic control of obese/diabetic mice. Methods: mice were treated for 4 months with a high fat diet (HF) and received a single i.c.v. injection of 26RFa (3 µg) or a chronic i.c.v. administration of the peptide during 28 days via osmotic minipumps (25 µg/day). i.p. and oral glucose tolerance tests, insulin tolerance test, glucose-stimulated insulin secretion, food/water intake, horizontal/vertical activity, energy expenditure, meal pattern and whole body composition were monitored. In addition, 26RFa and GPR103 mRNA expression as well as plasma 26RFa levels were evaluated by RT-QPCR and radioimmunoassay. Results: Acute administration of 26RFa in HF mice induced a robust anti-hyperglycemic effect by enhancing insulin secretion whereas chronic administration of the neuropeptide is unable to improve glucose homeostasis in these obese/diabetogenic conditions. By contrast, chronic 26RFa treatment induced an increase of the body weight accompanied with an enhanced food intake and a decreased energy expenditure. Finally, we show that the HF diet does not alter the hypothalamic expression of the 26RFa/GPR103 neuropeptidergic system nor the levels of circulating 26RFa. Conclusion: Our data indicate that the central beneficial effect of 26RFa on glucose homeostasis, by potentiating glucose-stimulated insulin secretion, is preserved in HF mice. However, chronic administration of the neuropeptide is unable to balance glycemia in these pathophysiological conditions, suggesting that the hypothalamic 26RFa/GPR103 neuropeptidergic system mainly affects short term regulation of glucose metabolism