RFamide Peptides 43RFa and 26RFa Both Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets but Exert Opposite Effects on Insulin Secretion

Granata, Riccarda; Settanni, Fabio; Trovato, Letizia; Gallo, Davide; Gesmundo, Iacopo; Nano, Rita; Gallo, Maria Pia; Bergandi, Loredana; Volante, Marco; Alloatti, Giuseppe; Piemonti, Lorenzo; Leprince, Jérôme; Papotti, Mauro; Vaudry, Hubert; Ong, Huy; Ghigo, Ezio

doi:10.2337/db13-1522

Cited by 46 publications

(80 citation statements)

References 49 publications

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“…Our data also show that 26RFa and GPR103 are expressed by the insulin-producing b-cells, suggesting an effect of the neuropeptide on b-cell activity. Consistent with this hypothesis, a recent study reports that 26RFa and GPR103 are expressed in the pancreatic islets and that 26RFa and its N-extended form, 43RFa, prevent b-cell death and apoptosis (30). The current study shows that 26RFa and its receptor are present in the same pancreatic islets, indicating that 26RFa may regulate b-cell activity via an autocrine mechanism.…”

Section: Discussionsupporting

confidence: 75%

“…Altogether, these findings indicate that 26RFa is able to stimulate insulin release by insulin-secreting cells via the activation of GPR103. Consistent with this finding, it has been recently reported that 43RFa, the N-extended form of 26RFa, stimulates insulin secretion by human pancreatic islets and INS-1E b-cells and that this effect is exerted via GPR103 (30). However, in the same study, the authors report that 26RFa inhibits insulin secretion via a signaling pathway distinct from GPR103, an observation previously made in rat perfused pancreas (31), and suggest that NPFF2 may mediate the insulinostatic activity of 26RFa.…”

Section: Discussionsupporting

confidence: 72%

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Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis

et al. 2015

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26RFa is a hypothalamic neuropeptide that promotes food intake. 26RFa is upregulated in obese animal models, and its orexigenic activity is accentuated in rodents fed a highfat diet, suggesting that this neuropeptide might play a role in the development and maintenance of the obese status. As obesity is frequently associated with type 2 diabetes, we investigated whether 26RFa may be involved in the regulation of glucose homeostasis. In the current study, we show a moderate positive correlation between plasma 26RFa levels and plasma insulin in patients with diabetes. Plasma 26RFa concentration also increases in response to an oral glucose tolerance test. In addition, we found that 26RFa and its receptor GPR103 are present in human pancreatic b-cells as well as in the gut. In mice, 26RFa attenuates the hyperglycemia induced by a glucose load, potentiates insulin sensitivity, and increases plasma insulin concentrations. Consistent with these data, 26RFa stimulates insulin production by MIN6 insulinoma cells. Finally, we show, using in vivo and in vitro approaches, that a glucose load induces a massive secretion of 26RFa by the small intestine. Altogether, the present data indicate that 26RFa acts as an incretin to regulate glucose homeostasis.26RFa and its N-extended form 43RFa (also referred to as QRFPs) are RFamide peptides discovered in the brain of various vertebrate species and identified as the cognate ligands of the human orphan G-protein-coupled receptor GPR103 (1-6). Neuroanatomical observations revealed that 26RFa-and GPR103-expressing neurons are primarily localized in hypothalamic nuclei involved in the control of feeding behavior (1,2,5,7). Indeed, intracerebroventricular administration of 26RFa or 43RFa stimulates food intake (1,5,8,9), and the neuropeptide exerts its orexigenic activity by modulating the neuropeptide Y/proopiomelanocortin system in the arcuate nucleus (9). Chronic injection of 43RFa induces a significant increase in mice body weight and fat mass, which is associated with a hyperphagic behavior (8), and the orexigenic activities of 26RFa and 43RFa are more robust in rodents fed a high-fat diet (8,10). Consistent with these observations, expression of prepro26RFa mRNA is upregulated in the hypothalamus of genetically obese ob/ob and db/db mice and rodents subjected to a high-fat diet (5,10). Altogether, these observations support the notion that 26RFa could play a role in the development and maintenance of the obese status.Obesity is frequently associated with type 2 diabetes, which is characterized by chronic hyperglycemia induced by impaired insulin secretion and increased insulin resistance (11-13). Accumulating evidence supports the

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Section: Discussionsupporting

confidence: 75%

Section: Discussionsupporting

confidence: 72%

Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis

et al. 2015

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“…The GPR103 gene (also designated as QRFPR gene) is a G-protein-coupled receptor that is expressed mostly in brain, but also in human pancreatic islets and it may have an effect on insulin secretion [31]. Moreover, the ligand for GPR103 (P518) is expressed in thyroid cells [32].…”

Section: Discussionmentioning

confidence: 99%

Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes

Tomer

Dolan

Kahaly

et al. 2015

Journal of Autoimmunity

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Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the cooccurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D+AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p<5×10−8). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D.

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“…In addition, these authors show that the inhibitory effect of 26RFa on exendin-4-induced insulin release is not observed in pancreas from pertussis toxin-treated rats suggesting the involvement of a pertussis toxin-sensitive G i protein negatively coupled to the adenylyl cyclase system (Egido et al, 2007). Recently, the role and mechanism of action of 26RFa/43RFa in the regulation of glucose metabolism has been studied more thoroughly (Granata et al, 2014; Prévost et al, 2015). The two studies show that 26RFa/43RFa and GPR103 are expressed by the pancreatic islets as well as by the rodent insulin-secreting cell lines INS-1E and MIN6.…”

Section: Rfa and Control Of Glucose Homeostasismentioning

confidence: 99%

The Neuropeptide 26RFa (QRFP) and Its Role in the Regulation of Energy Homeostasis: A Mini-Review

et al. 2016

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This mini-review deals with the neuropeptide 26RFa (or QRFP) which is a member of the RFamide peptide family discovered simultaneously by three groups in 2003. 26RFa (or its N-extended form 43RFa) was subsequently shown to be the endogenous ligand of the human orphan receptor GPR103. In the brain, 26RFa and GPR103mRNA are primarily expressed in hypothalamic nuclei involved in the control of feeding behavior, and at the periphery, the neuropeptide and its receptor are present in abundance in the gut and the pancreatic islets, suggesting that 26RFa is involved in the regulation of energy metabolism. Indeed, 26RFa stimulates food intake when injected centrally, and its orexigenic effect is even more pronounced in obese animals. The expression of 26RFa is up-regulated in the hypothalamus of obese animals, supporting that the 26RFa/GPR103 system may play a role in the development and/or maintenance of the obese status. Recent data indicate that 26RFa is also involved in the regulation of glucose homeostasis. 26RFa reduces glucose-induced hyperglycemia, increases insulin sensitivity and insulinemia. Furthermore, an oral ingestion of glucose strongly stimulates 26RFa release by the gut, indicating that 26RFa is a novel incretin. Finally, 26RFa is able to prevent pancreatic β cell death and apoptosis. This brief overview reveals that 26RFa is a key neuropeptide in the regulation of energy metabolism. Further fields of research are suggested including the pathophysiological implication of the 26RFa/GPR103 system.

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RFamide Peptides 43RFa and 26RFa Both Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets but Exert Opposite Effects on Insulin Secretion

Cited by 46 publications

References 49 publications

Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis

Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis

Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes

The Neuropeptide 26RFa (QRFP) and Its Role in the Regulation of Energy Homeostasis: A Mini-Review

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