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

Mehdi, El; Takhlidjt,; Khiar,; Prevost,; Rego, do; Benani,; Nedelec,; Godefroy,; Arabo,; Lefranc, Benjamin; Leprince,; Anouar,; Chartrel,; Picot,

doi:10.1101/816728

Cited by 3 publications

(7 citation statements)

References 31 publications

(54 reference statements)

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“…Finally, we reported that an oral glucose challenge induces a massive secretion of 26RFa by the gut into the blood, strongly suggesting that this neuropeptide regulates blood or plasma glucose by acting as an incretin [23]. This incretin effect of 26RFa has been confirmed by the observations that administration of a GPR103 antagonist reduces the global glucose-induced incretin effect and also decreases insulin sensitivity [25] and that 26RFa-deficient mice show impaired regulation of glucose homeostasis [26].…”

Section: Introductionmentioning

confidence: 77%

“…The mutant mice were generated by homologous recombination in embryonic stem cells of 129SvJ mice, which were then implanted in C57 blastocysts using standard procedures. The targeting vector was constructed by replacing the entire coding region of the prepro-26Rfa sequence in exon 2 of the 26Rfa gene with the iCre sequence and pgk-Neo cassette [26]. Insulin deficiency was induced by a single i.p.…”

Section: Methodsmentioning

confidence: 99%

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The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis

et al. 2022

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Aims/hypothesis 26RFa (pyroglutamilated RFamide peptide [QRFP]) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localised in the hypothalamus. In this study we investigated whether 26RFa neurons are involved in the hypothalamic regulation of glucose homeostasis. Methods 26Rfa +/+ , 26Rfa -/and insulin-deficient male C57Bl/6J mice were used in this study. Mice received an acute intracerebroventricular (i.c.v.) injection of 26RFa, insulin or the 26RFa receptor (GPR103) antagonist 25e and were subjected to IPGTTs, insulin tolerance tests, acute glucose-stimulated insulin secretion tests and pyruvate tolerance tests (PTTs). Secretion of 26RFa by hypothalamic explants after incubation with glucose, leptin or insulin was assessed. Expression and quantification of the genes encoding 26RFa, agouti-related protein, the insulin receptor and GPR103 were evaluated by quantitative reverse transcription PCR and RNAscope in situ hybridisation. Results Our data indicate that i.c.v.-injected 26RFa induces a robust antihyperglycaemic effect associated with an increase in insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26Rfa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26Rfa are mainly localised in the lateral hypothalamic area, that they co-express the gene encoding the insulin receptor and that insulin induces the expression of 26Rfa in these neurons. Concurrently, the central antihyperglycaemic effect of insulin is abolished in the presence of a GPR103 antagonist and in 26RFa-deficient mice. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. Conclusion/interpretationWe have identified a novel mechanism in the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system, and we provide evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

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Section: Introductionmentioning

confidence: 77%

Section: Methodsmentioning

confidence: 99%

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis

et al. 2022

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“…Finally, we reported that an oral glucose challenge induces a massive secretion of 26RFa by the gut into the blood, strongly suggesting that this neuropeptide regulates glycemia by acting as an incretin (23). This incretin effect of 26RFa has been very recently confirmed by the observation that administration of a GPR103 antagonist reduces the global glucose-induced incretin effect, and also decreases insulin sensitivity (25), and that 26RFa mutant mice show an impaired regulation of glucose homeostasis (26).…”

Section: Introductionmentioning

confidence: 78%

“…This incretin effect of 26RFa has been very recently confirmed by the observation that administration of a GPR103 antagonist reduces the global glucose-induced incretin effect, and also decreases insulin sensitivity (25), and that 26RFa mutant mice show an impaired 1 regulation of glucose homeostasis (26). 2…”

Section: Introductionmentioning

confidence: 82%

Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

Mehdi

Takhlidjt

Devere

et al. 2021

Preprint

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26RFa (QRFP) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localized in the hypothalamus. In the present study, we have investigated whether the 26RFa neurons may be involved in the hypothalamic regulation of glucose homeostasis. Our data indicate that 26RFa, i.c.v. injected, induces a robust antihyperglycemic effect associated with an increase of insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26RFa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26RFa in the lateral hypothalamic area and the ventromedial hypothalamic nucleus also express the insulin receptor and that insulin induces the expression of 26RFa in these neurons. Concurrently, we show that the central antihyperglycemic effect of insulin is abolished in presence of a 26RFa receptor (GPR103) antagonist as well as in mice deficient for 26RFa. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. To conclude, in the present study we have identified a novel actor of the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system and we provide the evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

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“…Total RNA from m-HypoA-59 cells and hypothalami was isolated as previously described [24]. Relative expression of the 26RFa, GPR103, insulin receptor, and IL6 genes was quantified by real-time PCR with appropriate primers (Table 1).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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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.

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

Cited by 3 publications

References 31 publications

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis

Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

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

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