Combined Deletion of Free Fatty-Acid Receptors 1 and 4 Minimally Impacts Glucose Homeostasis in Mice

Abstract

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.

Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion

“…S2E,F ). This is supported by recent studies suggesting that FFAR1 and FFAR4 signaling cooperate to stimulate insulin secretion ( Croze et al 2020 ). Neither FFAR1 ( Fig.…”

“…However, it is not entirely clear that FFAR1 and FFAR4 signaling results from precisely the same natural ligands, nor how typical dietary fluxes activate these individual receptors. Unlike FFAR4 agonists, FFAR1 agonists stimulate calcium influx, not cAMP ( Croze et al 2020 ). Synergy between cAMP and calcium signals appears common to various combinations of FFAR4, FFAR1, and GLP1R agonists ( Supplemental Fig.…”

Lipid-Induced Adaptations of the Pancreatic Beta-Cell to Glucotoxic Conditions Sustain Insulin Secretion

“…For instance, Latour et al observed no difference in glucose homeostasis between Ffar1 knockout and wild type mice, and their isolated islets were similarly sensitive to fatty acid inhibition of GSIS following 3 days of exposure to palmitate or oleate [ 95 ]. Similarly, Lan et al reported no difference between control and Ffar1 null mice fed either a standard chow diet or a high-fat diet [ 96 ], and the double knockout of Ffar1 and Ffar4 does not change the glucose tolerance in mice fed a high-fat diet, as recently shown by Croze et al [ 97 ]. Overexpression of the human FFAR1 in β-cells enhances insulin secretion and improves glucose tolerance both in mice fed a high-fat diet and in diabetic KK mice [ 98 ].…”

The Role of KLF2 in the Regulation of Atherosclerosis Development and Potential Use of KLF2-Targeted Therapy

“…GPR120 (free fatty acid receptor 4) is a receptor for free fatty acids (including omega-3), also known to suppress anti-inflammatory responses and insulin-sensitizing [ 69 , 70 ]. Thereby, GPR120 agonists (GW9508 and TUG-891) have been shown to mitigate ox-LDL-induced ECs dysfunction by suppressing OS and inflammation, inhibiting ROS production and expression of pro-inflammatory cytokines, VCAM-1 and E-selectin, induce KLF2 expression [ 71 ].…”