Anatomical distribution and biochemical characterization of the novel RFamide peptide 26RFa in the human hypothalamus and spinal cord

Bruzzone, Federica; Lectez, Benoît; Tollemer, Hélène; Leprince, Jérôme; Dujardin, Cynthia; Rachidi, Walid; Chatenet, David; Baroncini, Marc; Beauvillain, Jean-Claudé; Vallarino, Mauro; Vaudry, Hubert; Chartrel, Nicolas

doi:10.1111/j.1471-4159.2006.04090.x

Cited by 79 publications

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“…26RFa is a neuropeptide initially known to be produced by hypothalamic neurons (1,4,5) that cannot be responsible for the robust concentrations of the peptide detected in the blood (present data and 22). The observation that oral glucose load results in an increase of plasma 26RFa, as observed for incretins, suggested that the gastrointestinal tract may produce 26RFa.…”

Section: Discussionmentioning

confidence: 97%

“…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)(2)(3)(4)(5)(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).…”

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confidence: 99%

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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: Discussionmentioning

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

et al. 2015

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“…HPLC analysis combined with RIAs indicated the existence of both 26-and 43-amino acid residue RFamide peptide-like immunoreactivities in the hypothalamus and spinal cord of humans (Bruzzone et al 2006). Indeed, an N-terminally extended peptide of 43 residues, called 43RFa or QRFP, has been characterized in rat brain extracts, as well as in PC12 cells and the culture medium of CHO cells that express the human precursor, as described above (Fukusumi et al 2003, Bruzzone et al 2006, Takayasu et al 2006; Fig.…”

Section: Unity and Diversity Of The Structure Of 26rfa/qrfp In Vertebmentioning

confidence: 93%

“…A number of immunohistochemical studies that used antisera against FMRFamide suggested that the nervous system of vertebrates also contained neuropeptides immunologically related to FMRFamide (Raffathe neuropeptide FF (NPFF) group, the prolactin-releasing peptide (PrRP) group, the gonadotropin-inhibitory hormone (GnIH) group, the kisspeptin group, and the 26RFa/QRFP group (for reviews, see Ukena & Tsutsui (2005), Bruzzone et al (2006), Osugi et al (2006), , Tsutsui (2009), Tsutsui et al (2010a,b), Chartrel et al (2011), Leprince et al (2013); Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

MOLECULAR EVOLUTION OF GPCRS: 26Rfa/GPR103

Ukena¹,

Osugi²,

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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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“…Both peptides were identified as the cognate ligands of the orphan G-protein-coupled receptor 103 (GPR103) (6,7). 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).…”

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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

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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Anatomical distribution and biochemical characterization of the novel RFamide peptide 26RFa in the human hypothalamus and spinal cord

Cited by 79 publications

References 65 publications

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

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

MOLECULAR EVOLUTION OF GPCRS: 26Rfa/GPR103

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

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