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Abstract
Introduction 26RFa (pyroglutamyl RFamide peptide (QRFP)) is a biologically active peptide that has been found to control feeding behavior by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism.
Research design and methods 26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro26RFa was replaced by the iCre sequence. Energy and glucose metabolism was evaluated through measurement of complementary parameters. Morphological and physiological alterations of the pancreatic islets were also investigated.
Results Our data do not reveal significant alteration of energy metabolism in the 26RFa-deficient mice except the occurrence of an increased basal metabolic rate. By contrast, 26RFa mutant mice exhibited an altered glycemic phenotype with an increased hyperglycemia after a glucose challenge associated with an impaired insulin production, and an elevated hepatic glucose production. Two-dimensional and three-dimensional immunohistochemical experiments indicate that the insulin content of pancreatic β cells is much lower in the 26RFa−/− mice as compared with the wild-type littermates.
Conclusion Disruption of the 26RFa gene induces substantial alteration in the regulation of glucose homeostasis, with in particular a deficit in insulin production by the pancreatic islets. These findings further support the notion that 26RFa is an important regulator of glucose homeostasis.
- glucose-insulin homeostasis
- insulin secretion
- islet beta cell
- incretin
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Footnotes
Contributors ME-M, MP and NC contributed to study design and interpretation, and wrote the manuscript. J-LdR, J-CdR, FK, ST, AA, MP and ME-M performed the in vivo experiments on mice. ST, FK, DG and MP contributed to the immunohistochemical experiments and their quantitative analysis. FK and ME-M contributed to the PCR experiments. AB and EN performed the insulin assays, and JL produced the synthetic 26RFa. GP and YA revised and approved the final version of the manuscript. NC is the guarantor of this work, and as such had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) (grant number: U1239), the University of Rouen, the Institute for Research and Innovation in Biomedicine (IRIB) (recurrent funding), the ‘Fondation pour la Recherche Médicale’ (grant number: DEA 20140629966), and the ‘Société Francophone du Diabète’ (grant number: R16038EE). The present study was also cofunded by the European Union and the Normandie Regional Council. Europe gets involved in Normandie with European Regional Development Fund (ERDF).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All experimental procedures were approved by the Normandy Regional Ethics Committee (authorization: APAFIS#11752-2017100916177319) and were carried out in accordance with the European Committee Council Directive of November 24, 1986 (86/609/EEC).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.