GPR103b Functions in the Peripheral Regulation of Adipogenesis

Mulumba, Mukandila; Jossart, Christian; Granata, Riccarda; Gallo, Davide; Escher, Emanuel; Ghigo, Ezio; Servant, Marc J.; Marleau, Sylvie; Ong, Huy

doi:10.1210/me.2010-0010

Cited by 38 publications

(48 citation statements)

References 47 publications

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“…Interestingly, in a previous study, GPR103 was also detected in epididymal fat pads and shown to be elevated by 16-fold in high-fat mice (32). In addition, these authors showed, using 3T3-L1 adipocyte cells, that 26RFa elicits a dose-dependent increase in fatty acid uptake and increases the expression of genes involved in lipid uptake as well as triglyceride accumulation (32).…”

Section: Discussionmentioning

confidence: 92%

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: Discussionmentioning

confidence: 92%

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

et al. 2015

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“…Furthermore, QRFP expression in b-cells and human islets may suggest autocrine/paracrine effects of the peptides. Accordingly, 26RFa autocrine/paracrine effects have been recently proposed in prostate cancer cells, where the peptide induced cell migration and neuroendocrine differentiation, and in macrophages and adipocytes, where both 43RFa and 26RFa promoted adipogenesis (10,11,22). Future studies will help elucidate whether autocrine/paracrine mechanisms may also occur in pancreatic islets.…”

Section: Discussionmentioning

confidence: 93%

“…In humans and rodents, 43RFa, 26RFa, and GPR103 are mainly expressed in brain, particularly in the hypothalamus (8), as well as in peripheral tissues, including the eye, testis, thyroid, adipose tissue, and macrophages (6,(9)(10)(11). 43RFa and 26RFa have been implicated in many physiological functions, including stimulation of food intake (5,(12)(13)(14)(15)(16)(17), regulation of gonadotropic axis (18,19), aldosterone secretion (7,20), bone formation (21), adipogenesis and inflammation (10,11), blood pressure (12), and prostate cancer differentiation and migration (22).…”

mentioning

confidence: 99%

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

et al. 2014

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RFamide peptides 43RFa and 26RFa have been shown to promote food intake and to exert different peripheral actions through G-protein-coupled receptor 103 (GPR103) binding. Moreover, 26RFa was found to inhibit pancreatic insulin secretion, whereas the role of 43RFa on b-cell function is unknown, as well as the effects of both peptides on b-cell survival. Herein, we investigated the effects of 43RFa and 26RFa on survival and apoptosis of pancreatic b-cells and human pancreatic islets. In addition, we explored the role of these peptides on insulin secretion and the underlying signaling mechanisms. Our results show that in INS-1E b-cells and human pancreatic islets both 43RFa and 26RFa prevented cell death and apoptosis induced by serum starvation, cytokine synergism, and glucolipotoxicity, through phosphatidylinositol 3-kinase/Akt-and extracellular signal-related kinase 1/2-mediated signaling. Moreover, 43RFa promoted, whereas 26RFa inhibited, glucose-and exendin-4-induced insulin secretion, through Ga s and Ga i/o proteins, respectively. Inhibition of GPR103 expression by small interfering RNA blocked 43RFa insulinotropic effect, but not the insulinostatic action of 26RFa. Finally, 43RFa, but not 26RFa, induced cAMP increase and glucose uptake. In conclusion, because of their survival effects along with the effects on insulin secretion, these findings suggest potential for 43RFa and 26RFa as therapeutic targets in the treatment of diabetes.Pancreatic b-cell mass plays an essential role in glucose homeostasis. The reduced capacity of the endocrine pancreas to maintain an adequate insulin secretion, due to decreased b-cell mass and function, underlies both type 1 and type 2 diabetes (1). In type 1 diabetes, immunemediated release of inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interferon-g (IFN-g), and interleukin-1b (IL-1b) has been implicated in b-cell apoptosis (2). In type 2 diabetes, b-cell apoptosis results from the combined action of increased plasma glucose/free fatty acid levels (glucolipotoxicity) (3) and cytokines (4). Therefore, identifying molecules capable of increasing pancreatic b-cell survival may be crucial for the treatment and prevention of diabetes.RFamide-related peptides constitute a family of biologically active peptides terminating in arginine-phenylalanine-amide (Arg-Phe-NH 2 ) at their C-terminus. They include a 26-amino acid RFamide peptide (26RFa), which was isolated

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“…In the rat pancreas, glucose-evoked insulin secretion is reduced by perfusion of 26RFa/QRFP (Egido et al 2007). In the adipocyte cell line 3T3-L1, 26RFa/QRFP inhibits isoproterenol-induced lipolysis (Malumba et al 2010). As 3T3-L1 cells express the QRFPR-encoding gene, it appears that 26RFa/QRFP may act in an autocrine/paracrine manner to regulate adipogenesis (Malumba et al 2010).…”

Section: Comparative Aspects Of Biological Actions Of 26rfa/qrfp In Vmentioning

confidence: 99%

“…In the adipocyte cell line 3T3-L1, 26RFa/QRFP inhibits isoproterenol-induced lipolysis (Malumba et al 2010). As 3T3-L1 cells express the QRFPR-encoding gene, it appears that 26RFa/QRFP may act in an autocrine/paracrine manner to regulate adipogenesis (Malumba et al 2010). According to Alonzeau et al (2013), 26RFa/QRFP is also expressed in human prostate cancer and stimulates the neuroendocrine differentiation and migration of cancer cells.…”

Section: Comparative Aspects Of Biological Actions Of 26rfa/qrfp In Vmentioning

confidence: 99%

MOLECULAR EVOLUTION OF GPCRS: 26Rfa/GPR103

Ukena¹,

Osugi²,

Leprince³

et al. 2014

Journal of Molecular Endocrinology

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Neuropeptides possessing the Arg-Phe-NH 2 (RFamide) motif at their C-termini (designated as RFamide peptides) have been characterized in a variety of animals. Among these, neuropeptide 26RFa (also termed QRFP) is the latest member of the RFamide peptide family to be discovered in the hypothalamus of vertebrates. The neuropeptide 26RFa/QRFP is a 26-amino acid residue peptide that was originally identified in the frog brain. It has been shown to exert orexigenic activity in mammals and to be a ligand for the previously identified orphan G protein-coupled receptor, GPR103 (QRFPR). The cDNAs encoding 26RFa/QRFP and QRFPR have now been characterized in representative species of mammals, birds, and fish. Functional studies have shown that, in mammals, the 26RFa/QRFP-QRFPR system may regulate various functions, including food intake, energy homeostasis, bone formation, pituitary hormone secretion, steroidogenesis, nociceptive transmission, and blood pressure. Several biological actions have also been reported in birds and fish. This review summarizes the current state of identification, localization, and understanding of the functions of 26RFaQRFP and its cognate receptor, QRFPR, in vertebrates.

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GPR103b Functions in the Peripheral Regulation of Adipogenesis

Cited by 38 publications

References 47 publications

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

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

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

MOLECULAR EVOLUTION OF GPCRS: 26Rfa/GPR103

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