Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.04.236471v1?rss=1 Authors: Croze, M. L., Guillaume, A., Ethier, M., Fergusson, G., Ghislain, J., Poitout, V. Abstract: 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 beta-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. Copy rights belong to original authors. Visit the link for more info