Glucose homeostasis is impaired in mice deficient in the neuropeptide 26RFa (QRFP)

Abstract

Significance of this studyWhat is already known about this subject? ► 26RFa is a biologically active peptide produced in abundance in the gut and the pancreas. ► 26RFa has been found to regulate glucose homeostasis by acting as an incretin and by increasing insulin sensitivity.What are the new findings?► 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, assessing therefore the notion that 26RFa is an important regulator of glucose homeostasis.How might these results change the focus of research or clinical practice?► Identification of a novel actor in the regulation of glucose homeostasis is crucial to better understand the general control of glucose metabolism in physiological and pathophysiological conditions, and opens new fields of investigation to develop innovative drugs to treat diabetes mellitus. AbStrActIntroduction 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.

New Peptides as Potential Players in the Crosstalk Between the Brain and Obesity, Metabolic and Cardiovascular Diseases

“…Primeaux ( Takayasu et al, 2006 ) has shown that, after 3 weeks on a high-fat (55%) diet, consumption increased the concentration of preproQRFP mRNA in the VHM/ARC, but not in the LHA. In contrast, Beck et al ( El-Mehdi et al, 2020 ) have shown that the expression of 26RFa/QRFP was undetectable in Long-Evans rats fed on a high-fat diet, yet in the control group (30% fat) the expression was lower than in the low-fat (5%) diet group. Nevertheless, the application of a caloric restriction diet for 10 weeks in B6 mice resulted in no changes in the expression of 26RFa and GPR103 ( Méquinion et al, 2017 ).…”

“…Recently, the QRFP system is a popular target for research on metabolic homeostasis, glucose and lipid metabolism, pancreas function, and obesity ( Mulumba et al, 2010 , 2015 ; Méquinion et al, 2017 ; Prévost et al, 2019a , b ; El-Mehdi et al, 2020 ).…”

Associations of GWAS-Supported Non-MHC Genes with Autoimmune Thyroiditis in Patients with Type 1 Diabetes

“…The QRFPR gene (also known as GPR103 gene) encodes a G-protein-coupled receptor that is expressed in brain, urinary bladder, thyroid gland, human pancreatic β-cells, and so on. 21 Recent data indicate that QRFPR and its ligand QRFP are key regulators of glucose homeostasis 22 by increasing insulin sensitivity and insulin secretion, 23 , 24 as well as preventing pancreatic β-cells death and apoptosis. 25 Besides, a locus on chromosome 4q27 that is approximately 625kb downstream the QRFPR gene was reported to be associated with a number of autoimmune diseases.…”

Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study

“…N-methylation of Phe 22 (LV-2066, 25) and Phe 26 (LV-2242, 27) nullified the activity of the parent compound (EC 50 > 10 µM, Table 2) revealing the critical role of the corresponding NHs in forming an H-bond with the hQRFPR pocket residues or another residue of the peptide, whereas N-methylation of Phe 24 (LV-2233, 26) did not impair the whole activity of LV-2021 (1). The corresponding Tic-containing analogs (28)(29)(30) did not totally confirm these data since [Tic 24 ]26RFa (20)(21)(22)(23)(24)(25)(26) (20)(21)(22)(23)(24)(25)(26) (LV-2211, 28) was 5-fold more potent than 26RFa (20)(21)(22)(23)(24)(25)(26) (LV-2021, 1) (Figure 3D). It is thus also plausible that the structural constraint induced by the Tic 22 residue may keep the side chain in a favorable conformation for receptor activation, which was less accessible by free rotation in the native Phe side chain.…”

“…There is also evidence that 26RFa and/or QRFP regulate several other neuroendocrine and cognitive functions including reproduction [ 17 , 18 ], anxiety [ 19 ], memory [ 20 ], cardiovascular activity [ 8 ] and nociceptive transmission [ 21 , 22 , 23 ], some of which depend, at least in part, on off-target interaction with QRFPR-related receptors [ 24 , 25 ]. In addition, recent data reveal that the 26RFa/QRFPR system controls glucose homeostasis at the periphery by increasing insulin sensitivity and inhibiting hepatic glucose production [ 26 , 27 , 28 , 29 ]. Thus, QRFPR positions as an attractive target for the development of innovative drugs.…”