Objective Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. Methods Glucose tolerance tests were performed in mice after administration of selective GPR120 agonist Compound A. Insulin, glucagon, and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knock-out of gpr120 . Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β, and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively. Results Acute exposure to Compound A increased glucose tolerance, circulating insulin, and glucagon levels in vivo. Endogenous and/or pharmacological GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. Conclusions Inhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part by mitigating somatostatin release.
The free fatty-acid receptors FFAR1 (GPR40) and FFAR4 (GPR120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although GPR120 and GPR40 share similar ligands, few studies have addressed possible interactions between these 2 receptors in the control of glucose homeostasis. Here we generated mice deficient in gpr120 (Gpr120KO) or gpr40 (Gpr40KO), alone or in combination (Gpr120/40KO), and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective GPR120 and GPR40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120KO females. Fasting blood glucose levels were mildly increased in Gpr120/40KO mice and in a sex-dependent manner in Gpr120KO and Gpr40KO animals. Oral glucose tolerance was slightly reduced in male Gpr120/40KO mice and in Gpr120KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate was lower in male Gpr120/40KO mice, but insulin and c-peptide levels were unaffected. No changes in glucose tolerance were observed in either single or double knock-out animals under high-fat feeding. In isolated islets from wild-type mice, the combination of selective GPR120 and GPR40 agonists additively increased insulin secretion. We conclude that while simultaneous activation of GPR120 and GPR40 enhances insulin secretion ex vivo, combined deletion of these 2 receptors only minimally affects glucose homeostasis in vivo in mice.
Objective: Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free-fatty acid receptor 4 (FFAR4/Gpr120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of Gpr120 remains unclear. As Gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that Gpr120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. Methods: Glucose tolerance tests were performed in mice after administration of the selective Gpr120 agonist Cpd A. Gpr120 mRNA levels were assessed in pancreatic section by RNA in situ hybridization. Insulin, glucagon and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and pharmacological (Compound A and AZ-13581837) Gpr120 agonists. The effect of Compound A on hormone secretion was tested in islets isolated from mice with global or somatostatin cell-specific knockout (KO) of Gpr120. Calcium and cAMP dynamics in response to pharmacological Gpr120 agonists were measured in islets isolated from α, β, and δ cell-specific GCaMP6 and CAMPER reporter mice, respectively. Results: Acute exposure to Compound A increased glucose tolerance and circulating insulin and glucagon levels in vivo. Both pharmacological and endogenous Gpr120 agonists dose-dependently potentiated glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion and concomitantly reduced somatostatin secretion in isolated islets. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of Gpr120, and was partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. Gpr120 agonists reduced forskolin-stimulated cAMP levels in δ cells, but did not evoke calcium signaling in islet cells. Conclusions: This study supports a key contribution of inhibitory Gpr120-Gαi/o signaling in δ cells in both insulin and glucagon secretion in part via mitigating somatostatin release.
The fatty-acid receptors FFAR1 (Gpr40) and FFAR4 (Gpr120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although the properties of Gpr120 and Gpr40 converge on glucose homeostasis, few studies have addressed possible interactions between these two receptors in the control of β cell function. Here we generated mice deficient in Gpr120 or Gpr40, alone or in combination, and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective Gpr120 and Gpr40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120 knockout (KO) females. Fasting blood glucose levels increased in Gpr120/40 double KO mice, and in a sex-dependent manner in Gpr120 KO and Gpr40 KO animals. Oral glucose tolerance was reduced in Gpr120/40 double KO male mice and in Gpr120 KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate and disposition index were lower in Gpr120/40 double KO. In contrast, we did not observe changes in glucose tolerance in either single or double KO animals under high-fat feeding. In isolated wild-type islets, the combination of selective Gpr120 and Gpr40 agonists additively increased insulin secretion compared to each agonist alone. We conclude that Gpr120 and Gpr40 cooperate in an additive manner to regulate glucose homeostasis and insulin secretion in male mice.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.