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GPR119 Is Required for Physiological Regulation of Glucagon-Like Peptide-1 Secretion but Not for Metabolic Homeostasis

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GPR119 Is Required for Physiological Regulation of Glucagon-Like Peptide-1 Secretion but Not for Metabolic Homeostasis 219 GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis Hong Lan1, Galya Vassileva2, Aaron Corona1, Li Liu1, Hana Baker1, Andrei Golovko2, Susan J Abbondanzo2, Weiwen Hu2, Shijun Yang2, Yun Ning1, Robert A Del Vecchio3, Frederique Poulet4, Maureen Laverty2, Eric L Gustafson2, Joseph A Hedrick1 and Timothy J Kowalski1 Departments of 1Cardiovascular and Metabolic Disease Research, 2Discovery Technologies 3Neurobiology and 4Drug Safety, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA (Correspondence should be addressed to H Lan; Email: [email protected]; T J Kowalski; Email: [email protected]) Abstract G protein-coupled receptor 119 (GPR119) is expressed in that GPR119 plays a role in physiological regulation of GLP-1 C C pancreatic islets and intestine, and is involved in insulin and secretion. Under HFD-feeding, both Gpr119 / and K K K K incretin hormone release. GPR119-knockout (Gpr119 / ) Gpr119 / mice gain weight similarly, develop hyperinsuli- mice were reported to have normal islet morphology and nemia and hyperleptinemia, but not hyperglycemia or normal size, body weight (BW), and fed/fasted glucose levels. dyslipidemia. Glucose and insulin tolerance tests did not reveal However, the physiological function of GPR119 and its role in a genotypic difference. These data show that GPR119 is not maintaining glucose homeostasis under metabolic stress essential for the maintenance of glucose homeostasis. More- remain unknown. Here, we report the phenotypes of an over, we found that oleoylethanolamide (OEA), reported as a K K independently generated line of Gpr119 / mice under basal ligand for GPR119, was able to suppress food intake in both C C K K and high-fat diet (HFD)-induced obesity. Under low-fat diet Gpr119 / and Gpr119 / mice, indicating that GPR119 is K K feeding, Gpr119 / mice show normal plasma glucose and not required for the hypophagic effect of OEA. Our results lipids, but have lower BWs and lower post-prandial levels of demonstrate that GPR119 is important for incretin and insulin active glucagon-like peptide 1 (GLP-1). Nutrient-stimulated secretion, but not for appetite suppression. K/K GLP-1 release is attenuated in Gpr119 mice, suggesting Journal of Endocrinology (2009) 201, 219–230 Introduction The G protein-coupled receptor 119 (GPR119), first identified through a bioinformatics approach (Fredriksson Type 2 diabetes is characterized by insulin resistance with et al. 2003), is predominantly expressed in pancreatic islets insufficient compensatory insulin secretion from pancreatic and b-cell lines (Soga et al. 2005, Sakamoto et al. 2006, Chu islet b-cells (Kasuga 2006). In accordance with the two et al. 2007, 2008). The fatty acid derivatives oleoyl- components of type 2 diabetes, pharmacological treatments lysophosphatidylcholine (LPC) and oleoylethanolamide fall into two major categories: drugs that improve insulin (OEA) have been proposed as endogenous ligands of sensitivity, and those that increase insulin secretion from GPR119. LPC has been shown to increase cAMP and b-cells. Agents that enhance insulin secretion in a glucose- enhance glucose stimulated insulin secretion in NIT-1 dependent manner, such as glucagon-like peptide-1 (GLP-1) insulinoma cells and perfused rat pancreas respectively, and GPR119 siRNA partially blunted the effect of LPC on mimetics (e.g. Exendin-4 (Ex-4)), are desirable because they glucose-stimulated insulin secretion (GSIS) in NIT-1 cells do not carry the risk of causing hypoglycemia (Drucker (Soga et al. 2005). Recently, our lab showed that in glucose- 2006). Likewise, agents that inhibit dipeptidyl peptidase IV insensitive rat insulinoma RIN m5f cells, LPC appears to (DPP-IV), the enzyme responsible for degrading the incretins increase insulin release through both GPR119-dependent GLP-1 and gastric inhibitory polypeptide (GIP) have also and -independent mechanisms (Ning et al. 2008). On the emerged as novel type 2 diabetes therapeutics (Sinclair & other hand, OEA is a naturally occurring fatty acid amide Drucker 2005). The successful development of drugs with diverse biological functions, among which are targeting the GLP-1 receptor has promoted more research regulation of satiety and body weight (BW; Fu et al. on other G protein-coupled receptors (GPCRs) expressed in 2003). Overton et al. (2006, 2008) identified OEA, together pancreatic b-cells. with two synthetic compounds, as ligands of GPR119. In a Journal of Endocrinology (2009) 201, 219–230 DOI: 10.1677/JOE-08-0453 0022–0795/09/0201–219 q 2009 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/26/2021 10:54:19PM via free access K/K 220 H LAN and others . Characterization of Gpr119 mice yeast-based reporter assay, OEA displays EC50 values of Gpr119 locus were sub-cloned into a vector at either end of 3.2 mM for human GPR119 and 2.9 mM for mouse the neomycin resistance gene (neo). This targeting vector GPR119. They proposed that the hypophagic effect of was linearized and electroporated into C57BL/6J derived ES OEA in rat was mediated by GPR119, but the effect of OEA cells. Colonies resistant to G-418 were screened for the on activating pancreatic GPR119 or on insulin secretion targeted Gpr119 gene by a PCR-based strategy using one were not reported. We recently showed that OEA increases primer (50-taagtccaggattggcgcaga-30), corresponding to a insulin release from RIN m5f cells transfected with human region upstream of the Gpr119 gene, and another primer GPR119 and also potentiates GSIS in mouse insulinoma (50-cgccccgactgcatctgcgtgtt-30), corresponding to the Min6 c4 cells (Ning et al. 2008); however, the efficacy and neomycin resistance gene. The predicted structure of the specificity of LPC or OEA as GPR119 ligands has not been targeted Gpr119 locus in the PCR-positive cells was examined in primary islets. confirmed by Southern blotting, using probes that hybridize Recently, investigators at Arena Pharmaceuticals demon- outside of and adjacent to the construct arms. Cells strated that a potent GPR119 agonist (AR231453) enhanced from several correctly targeted ES cell lines were injected GSIS, and improved oral glucose tolerance in lean, diabetic into C57BL/6J-Tyrc-2J/J blastocysts to generate chimeric Leprdb/db, and KK/Ay mice (Chu et al. 2007). In a follow-up mice. Chimeras obtained from these clones were then bred C K study, Chu et al. (2008) reported that GPR119 is also with C57BL/6J mice to generate heterozygous (Gpr119 / ) expressed at low levels in intestinal endocrine cells, and that its offspring that were further bred in order to obtain K K activation by AR231453 contributes to glycemic control by homozygous (Gpr119 / ) mice. We used a PCR-based enhancing GLP-1 and GIP release. The specificity of screening strategy with three oligonucleotide primers in AR231453 was demonstrated by the absence of effects on a multiplex reaction corresponding to the region of glucose tolerance and GLP-1 release in GPR119-deficient homology, the neo gene, and the deleted region of the mice (Chu et al. 2007, 2008). Unlike OEA (Overton et al. Gpr119 gene. These primers were designed to detect 2006), AR231453 was observed to suppress food intake only both wild-type (573 bp) and targeted (402 bp) alleles. at doses significantly higher than those required to impact Oligonucleotide sequences were as follows: Gpr119 deleted glucose homeostasis (Chu et al. 2007). region forward 50-ttccagcagaccacctaccat-30, Gpr119 arm of Although the therapeutic potential of GPR119 has been homology reverse 50-ttagccatcgagctccggatggctg-30, and neo established through activation by endogenous and pharma- 50-cgccccgactgcatctgcgtgtt-30. cological agents, its physiological function remains unclear All mice under study were weaned onto Lab Rodent Diet (Lauffer et al. 2008). Deletion of GPR119 appears to have no 20 (PMI Nutrition International, Brentwood, MO, USA overt effect on glucose homeostasis under normal conditions. LLC; 4.5% fat) and, unless specified, were group housed in The limited characterization of the GPR119 knockout mice polycarbonate cages in a specific pathogen-free environment reported by Arena researchers showed that islet morphology on a 12 h light:12 h darkness cycle at a temperature of 22 8C. and responsiveness to glucose and GLP-1 were normal, as were For experiments exploring the effect of genotype in response BW and fed/fasted glucose levels, indicating that deletion to manipulation of dietary fat content, mice were fed with a of GPR119 does not grossly impact glucose homeostasis (Chu semi-purified high-fat diet (HFD; 45% of calories from fat) or et al. 2007, 2008). However, it is unclear if GPR119 is required a semi-purified low-fat diet (LFD; 10% of calories from fat; to maintain lipid and glucose homeostasis under conditions of D12451 and D12450B respectively; Research Diets, New metabolic stress such as diet-induced obesity. Brunswick, NJ, USA) ad libitum unless otherwise indicated. In We carried out a systematic characterization of indepen- one cohort of mice, HFD-feeding was initiated at 70 days of K K dently generated Gpr119 / mice on the C57BL/6J age and mice remained on the diet for 36 weeks. In a second background. Our results demonstrate that GPR119 is not cohort of mice, the LFD- or HFD-feeding was initiated at required to maintain lipid and glucose homeostasis, but it is 6–8 weeks of age and continued for 33 weeks. Blood involved in nutrient-stimulated GLP-1 release. We also show collection after an overnight fast was performed after 31 weeks that LPC and OEA are non-specific GPR119 agonists in on the diet, and blood collection in the post-prandial state was terms of their insulinotropic effect and hypophagic effect performed after 33 weeks on diet. All studies were conducted in respectively. an American Association for Laboratory Animal Care accredited facility, according to protocols approved by the Schering- Plough Research Institute Animal Care and Use Committee.
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