Didier Bagnol

A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release.

We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement of glucose-dependent insulin release in pancreatic beta-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1. Furthermore, in situ hybridization studies indicated that most GLP-1-producing cells coexpress GPR119 mRNA. In GLUTag cells, a well-established model of intestinal L-cell function, the potent GPR119 agonist AR231453 stimulated cAMP accumulation and GLP-1 release. When administered in mice, AR231453 increased active GLP-1 levels within 2 min after oral glucose delivery and substantially enhanced total glucose-dependent insulinotropic peptide levels. Blockade of GLP-1 receptor signaling with exendin(9-39) reduced the ability of AR231453 to improve glucose tolerance in mice. Conversely, combined administration of AR231453 and the DPP-4 inhibitor sitagliptin to wild-type mice significantly amplified both plasma GLP-1 levels and oral glucose tolerance, relative to either agent alone. In mice lacking GPR119, no such enhancement was seen. Thus, GPR119 regulates glucose tolerance by acting on intestinal endocrine cells as well as pancreatic beta-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy.

Arcuate Glucagon-Like Peptide 1 Receptors Regulate Glucose Homeostasis but Not Food Intake

OBJECTIVE—Glucagon-like peptide-1 (GLP-1) promotes glucose homeostasis through regulation of islet hormone secretion, as well as hepatic and gastric function. Because GLP-1 is also synthesized in the brain, where it regulates food intake, we hypothesized that the central GLP-1 system regulates glucose tolerance as well. RESEARCH DESIGN AND METHODS—We used glucose tolerance tests and hyperinsulinemic-euglycemic clamps to assess the role of the central GLP-1 system on glucose tolerance, insulin secretion, and hepatic and peripheral insulin sensitivity. Finally, in situ hybridization was used to examine colocalization of GLP-1 receptors with neuropeptide tyrosine and pro-opiomelanocortin neurons. RESULTS—We found that central, but not peripheral, administration of low doses of a GLP-1 receptor antagonist caused relative hyperglycemia during a glucose tolerance test, suggesting that activation of central GLP-1 receptors regulates key processes involved in the maintenance of glucose homeostasis. Central administration of GLP-1 augmented glucose-stimulated insulin secretion, and direct administration of GLP-1 into the arcuate, but not the paraventricular, nucleus of the hypothalamus reduced hepatic glucose production. Consistent with a role for GLP-1 receptors in the arcuate, GLP-1 receptor mRNA was found to be expressed in 68.1% of arcuate neurons that expressed pro-opiomelanocortin mRNA but was not significantly coexpressed with neuropeptide tyrosine. CONCLUSIONS—These data suggest that the arcuate GLP-1 receptors are a key component of the GLP-1 system for improving glucose homeostasis by regulating both insulin secretion and glucose production.

Diet‐Induced Models of Obesity (DIO) in Rodents

Obesity results from a complex interplay between a susceptible genotype and an environment that both promotes increased caloric intake and enables sustained decreases in energy expenditure. One commonly employed approach to modeling obesity in preclinical species is the diet‐induced obese (DIO) rodent. Here, theoretical and practical considerations for producing obese rodents via dietary manipulation, and for assessing drug‐induced changes in food intake and body weight are described. Based on these considerations, a standardized protocol for diet‐induced obesity in both mouse and rat is provided and sample data from these models are also described. Curr. Protoc. Neurosci. 59:9.38.1‐9.38.13.

The Arg–Phe‐amide peptide 26RFa/glutamine RF‐amide peptide and its receptor: IUPHAR Review 24

The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross‐reactivity with antibodies raised against bovine neuropeptide FF (NPFF). 26RFa and its N‐terminally extended form glutamine RF‐amide peptide (QRFP) have been identified as cognate ligands of the former orphan receptor GPR103, now renamed glutamine RF‐amide peptide receptor (QRFP receptor). The 26RFa/QRFP precursor has been characterized in various mammalian and non‐mammalian species. In the brain of mammals, including humans, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While humans express only one QRFP receptor, two isoforms are present in rodents. The QRFP receptor genes are widely expressed in the CNS and in peripheral tissues, notably in bone, heart, kidney, pancreas and testis. Structure–activity relationship studies have led to the identification of low MW peptidergic agonists and antagonists of QRFP receptor. Concurrently, several selective non‐peptidic antagonists have been designed from high‐throughput screening hit optimization. Consistent with the widespread distribution of QRFP receptor mRNA and 26RFa binding sites, 26RFa/QRFP exerts a large range of biological activities, notably in the control of energy homeostasis, bone formation and nociception that are mediated by QRFP receptor or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP‐QRFP receptor system and discusses the potential use of selective QRFP receptor ligands for therapeutic applications.

The Arg-Phe-amide peptide 26RFa/QRFP and its Receptor. IUPHAR Review

The RFamide neuropeptide 26RFa was first isolated from the brain of the European green frog on the basis of cross‐reactivity with antibodies raised against bovine neuropeptide FF (NPFF). 26RFa and its N‐terminally extended form glutamine RF‐amide peptide (QRFP) have been identified as cognate ligands of the former orphan receptor GPR103, now renamed glutamine RF‐amide peptide receptor (QRFP receptor). The 26RFa/QRFP precursor has been characterized in various mammalian and non‐mammalian species. In the brain of mammals, including humans, 26RFa/QRFP mRNA is almost exclusively expressed in hypothalamic nuclei. The 26RFa/QRFP transcript is also present in various organs especially in endocrine glands. While humans express only one QRFP receptor, two isoforms are present in rodents. The QRFP receptor genes are widely expressed in the CNS and in peripheral tissues, notably in bone, heart, kidney, pancreas and testis. Structure–activity relationship studies have led to the identification of low MW peptidergic agonists and antagonists of QRFP receptor. Concurrently, several selective non‐peptidic antagonists have been designed from high‐throughput screening hit optimization. Consistent with the widespread distribution of QRFP receptor mRNA and 26RFa binding sites, 26RFa/QRFP exerts a large range of biological activities, notably in the control of energy homeostasis, bone formation and nociception that are mediated by QRFP receptor or NPFF2. The present report reviews the current knowledge concerning the 26RFa/QRFP‐QRFP receptor system and discusses the potential use of selective QRFP receptor ligands for therapeutic applications.