GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

Pachanski, Michele; Kirkland, Melissa; Kosinski, Daniel; Mane, Joel; Cheewatrakoolpong, Boonlert; Xue, Jiyan; Szeto, Daphne; Forrest, Gail; Miller, Corin; Bunzel, Michelle; Plummer, Christopher W.; Chobanian, Harry R.; Miller, Mark W.; Souza, Sarah; Thomas-Fowlkes, Brande; Ogawa, Aimie M.; Weinglass, Adam B.; Salvo, Jerry Di; Li, Xiaoyan; Feng, Yue; Tatosian, Daniel; Howard, Andrew D.; Colletti, Steven L.; Trujillo, María E.

doi:10.1371/journal.pone.0186033

Cited by 17 publications

(17 citation statements)

References 27 publications

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“…In DIO-F344 rats given T-3601386 for 4 weeks, significant increases in plasma GLP-1 levels were observed following the single dose of T-3601386 (Fig 3D and 3E) , suggesting the continuous elevation of plasma GLP-1 levels during the repeated dosing study. These results are consistent with a previous report that a GPR40 full agonist exerts BW-lowering effect with the augmentation of circulating GLP-1 [16] .…”

Section: Resultssupporting

confidence: 94%

“…In the GI tract, GPR40 has been reported to co-localize not only with GLP-1 and GIP but also with other intestinal hormones [44] , and in fact, peptide YY (PYY) secretion was observed after dosing with other full agonists [16, 17] . Previous reports suggested that a novel strategy through dual receptor agonism of GLP-1/GIP or GLP-1/PYY would lead to a greater BW loss with anti-diabetic effects than each mono-hormonal therapy [45, 46] .…”

Section: Discussionmentioning

confidence: 99%

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GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve

et al. 2019

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GPR40/FFAR1 is a Gq protein-coupled receptor expressed in pancreatic β cells and enteroendocrine cells, and mediates insulin and incretin secretion to regulate feeding behavior. Several GPR40 full agonists have been reported to reduce food intake in rodents by regulating gut hormone secretion in addition to their potent glucose-lowering effects; however, detailed mechanisms of feeding suppression are still unknown. In the present study, we characterized T-3601386, a novel compound with potent full agonistic activity for GPR40, by using in vitro Ca2+ mobilization assay in Chinese hamster ovary (CHO) cells expressing FFAR1 and in vivo hormone secretion assay. We also evaluated feeding suppression and weight loss after the administration of T-3601386 and investigated the involvement of the vagal nerve in these effects. T-3601386, but not a partial agonist fasiglifam, increased intracellular Ca2+ levels in CHO cells with low FFAR1 expression, and single dosing of T-3601386 in diet-induced obese (DIO) rats elevated plasma incretin levels, suggesting full agonistic properties of T-3601386 against GPR40. Multiple doses of T-3601386, but not fasiglifam, in DIO rats showed dose-dependent weight loss accompanied by feeding suppression and durable glucagon-like peptide-1 elevation, all of which were completely abolished in Ffar1-/- mice. Immunohistochemical analysis in the nuclei of the solitary tract demonstrated that T-3601386 increased the number of c-Fos positive cells, which also disappeared in Ffar1-/- mice. Surgical vagotomy and drug-induced deafferentation counteracted the feeding suppression and weight loss induced by the administration of T-3601386. These results suggest that T-3601386 exerts incretin release and weight loss in a GPR40-dependent manner, and that afferent vagal nerves are important for the feeding suppression induced by GPR40 full agonism. Our novel findings raise the possibility that GPR40 full agonist can induce periphery-derived weight reduction, which may provide benefits such as less adverse effects in central nervous system compared to centrally-acting anti-obesity drugs.

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Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve

et al. 2019

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“…Although a further study is essential to elucidate the mechanism by which GPR40 agonism regulates food intake and body weight, this property of SCO-267 may be beneficial in patients who are overweight or obese and have type 2 diabetes. SCO-267 stimulated glucagon secretion in rats, which is consistent with a previous study using a GPR40 full agonist (Pachanski et al, 2017). This suggests that GPR40 full agonists exhibit a direct targeted effect on glucagon secretion.…”

Section: Discussionsupporting

confidence: 91%

SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity

Ueno

Ito

Abe

et al. 2019

J Pharmacol Exp Ther

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The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca 21 signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/-) mice. Treatment with SCO-267 activated Gq signaling in both high-and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/mice, indicating a GPR40dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.

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“…Recent data are still highly polarized, with some authors supporting ( 255 ), and others disproving this ( 256 ), or even indicating that GPR40 protects β-cells from lipotoxicity ( 257 ) rendering difficult to draw any conclusive mechanistic involvement in healthy and diabetic individuals. Nonetheless, the activation of this receptor with FFAs has demonstrated to induce the secretion of incretins ( 79 , 258 ) glucagon ( 78 , 250 ) and partially glucose-stimulated insulin ( 259 , 260 ) reducing food intake, and lowering body weight in animals models ( 261 ). Mice without a functional GPR40 display an impaired CCK and GLP-1 secretion after an oil gavage, while surprisingly animals deficient for GPR120 display a normal corn oil-induced GLP-1 secretion ( 80 , 262 ).…”

Section: Long and Middle Chain Fatty Acid Receptorsmentioning

confidence: 99%

Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1

Paternoster

Falasca

2018

Front. Endocrinol.

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An aging world population exposed to a sedentary life style is currently plagued by chronic metabolic diseases, such as type-2 diabetes, that are spreading worldwide at an unprecedented rate. One of the most promising pharmacological approaches for the management of type 2 diabetes takes advantage of the peptide hormone glucagon-like peptide-1 (GLP-1) under the form of protease resistant mimetics, and DPP-IV inhibitors. Despite the improved quality of life, long-term treatments with these new classes of drugs are riddled with serious and life-threatening side-effects, with no overall cure of the disease. New evidence is shedding more light over the complex physiology of GLP-1 in health and metabolic diseases. Herein, we discuss the most recent advancements in the biology of gut receptors known to induce the secretion of GLP-1, to bridge the multiple gaps into our understanding of its physiology and pathology.

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GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

Cited by 17 publications

References 27 publications

GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve

GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve

SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity

Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1

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