Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival

The regulation of pancreatic beta cell mass is a critical factor to help maintain normoglycemia during insulin resistance. Nutrient-sensing G protein-coupled receptors (GPCR) contribute to aspects of beta cell function, including regulation of beta cell mass. Nutrients such as free fatty acids (FFAs) contribute to precise regulation of beta cell mass by signaling through cognate GPCRs, and considerable evidence suggests that circulating FFAs promote beta cell expansion by direct and indirect mechanisms. Free Fatty Acid Receptor 2 (FFA2) is a beta cell-expressed GPCR that is activated by short chain fatty acids, particularly acetate. Recent studies of FFA2 suggest that it may act as a regulator of beta cell function. Here, we set out to explore what role FFA2 may play in regulation of beta cell mass. Interestingly, Ffar2(-/-) mice exhibit diminished beta cell mass at birth and throughout adulthood, and increased beta cell death at adolescent time points, suggesting a role for FFA2 in establishment and maintenance of beta cell mass. Additionally, activation of FFA2 with G alpha(q/11)-biased agonists substantially increased beta cell proliferation in in vitro and ex vivo proliferation assays. Collectively, these data suggest that FFA2 may be a novel therapeutic target to stimulate beta cell growth and proliferation.