Acute but Not Chronic Central Administration of the Neuropeptide 26RFa (QRFP) Improves Glucose Homeostasis in Obese/Diabetic Mice

Abstract

Introduction: 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.

An analogue of the Prolactin Releasing Peptide reduces obesity and promotes adult neurogenesis

“…This ability of LiPR to normalize metabolomic response to HFD is further highlighted by our RNAseq data. LiPR upregulated expression of genes related to energy homeostasis and development of obesity such as Qrfp and Afm (Juhasz et al, 2022 ; Le Solliec et al, 2022 ) or genes involved in the regulation of insulin or thyroid hormone expression and distribution such as Lmx1a and Ttr (German et al, 1992 ; Liz et al, 2020 ) In addition to its role in metabolism, LiPR also downregulated expression of pro-inflammatory cytokine, Il31ra (Nemmer et al, 2021 ) and influenced expression of Tmed7, which controls trafficking of Toll-like receptor 4 (Trl4), a key receptor in innate immunity (Liaunardy-Jopeace et al, 2014 ). This suggests that LiPR plays an anti-inflammatory role previously observed in a model of neurodegeneration (Holubova et al, 2019 ).…”

An analogue of the Prolactin Releasing Peptide reduces obesity and promotes adult neurogenesis

“…This ability of LiPR to normalize metabolomic response to HFD is further highlighted by our RNAseq data. LiPR upregulated expression of genes related to energy homeostasis and development of obesity such as Qrfp and Afm 67,68 or genes involved in regulation of insulin or thyroid hormone expression and distribution such as Lmx1a and Ttr. 69,70 In addition to its role in metabolism, LiPR also downregulated expression of pro-inflammatory cytokine, Il31ra 71 and influenced expression of Tmed7, which controls trafficking of Toll-like receptor 4 (Trl4), a key receptor in innate immunity.…”