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

Abstract

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

The diet‐derived short chain fatty acid propionate improves beta‐cell function in humans and stimulates insulin secretion from human islets in vitro

“…Thus, it has been reported that a phenylacetamide derivative agonist of FFAR2 enhances β-cell proliferation, 14 FFAR2 knockout mice show reduced β-cell expansion during pregnancy, 27 and a FFAR2 agonist that preferentially couples via Gq promotes mouse islet β-cell proliferation. 28 Consistent with SCFAs playing an important role in maintaining β-cell mass, we have In summary, we have demonstrated that increasing colonic propionate improves β-cell function in vivo, and our in vitro observations in human islets indicate that this may occur both via short-term acute effects of propionate to directly stimulate insulin secretion and through its longer-term effects to protect β-cells from apoptotic stimuli. These data support the ingestion of propiogenic dietary fibres to maintain healthy glucose homeostasis, both through the established beneficial effects via elevations in GLP-1 and PYY 16 and by the novel signalling identified here, of direct stimulatory effects of propionate at β-cells.…”

“…Recent studies in mice have indicated direct signalling via FFAR2 in islets to regulate β‐cell mass. Thus, it has been reported that a phenylacetamide derivative agonist of FFAR2 enhances β‐cell proliferation, FFAR2 knockout mice show reduced β‐cell expansion during pregnancy, and a FFAR2 agonist that preferentially couples via Gq promotes mouse islet β‐cell proliferation . Consistent with SCFAs playing an important role in maintaining β‐cell mass, we have demonstrated, for the first time, that propionate significantly reduced human islet apoptosis induced by sodium palmitate and by cytokines.…”

Short chain fatty acids stimulate insulin secretion and reduce apoptosis in mouse and human islets in vitro: Role of free fatty acid receptor 2

“…Although FFAR2 and FFAR3 deletion is reported to improve glucose tolerance in obese mice, it has also been reported that FFAR2 −/− mice fed a high‐fat diet show no changes in glucose tolerance and that obese and pregnant FFAR2 −/− mice develop glucose intolerance, so it is not clear from published studies whether FFAR2 improves or impairs glucose homeostasis. The observation that FFAR2 −/− mice have reduced β‐cell mass at birth suggests a role for FFAR2 in β‐cell development, and the reduced β‐cell area was also observed in adulthood . However, β‐cell proliferation is elevated in FFAR2 −/− mice and deletion of FFAR2 does not impair glucose tolerance in mice fed normal chow, suggesting that FFAR2 is not essential for normal glucose homeostasis.…”

“…In particular, we and others have identified that FFAR2 and FFAR3 are expressed by islets of Langerhans, opening up the possibility that SCFAs contribute to the regulation of insulin secretion through activation of these receptors. However, the data published so far do not provide a consensus role for SCFAs and their receptors in islets: the first paper published in this area reported that acetate inhibited insulin release in vitro and that deletion of FFAR2 and FFAR3 improved glucose tolerance, while there have been more recent reports of SCFAs stimulating insulin secretion and of deletion of FFAR2 being associated with insufficient β‐cell mass expansion in obesity and gestational diabetes . Acetate is the most abundant circulating SCFA, reaching plasma concentrations of ~200 μM, while propionate concentrations are ~10‐fold lower, and these are the two SCFAs that are used most commonly for experimental studies.…”

“…However, the data published so far do not provide a consensus role for SCFAs and their receptors in islets: the first paper published in this area reported that acetate inhibited insulin release in vitro and that deletion of FFAR2 and FFAR3 improved glucose tolerance, 7 while there have been more recent reports of SCFAs stimulating insulin secretion and of deletion of FFAR2 being associated with insufficient β-cell mass expansion in obesity and gestational diabetes. 5,6,[8][9][10][11][12] Acetate is the most abundant circulating SCFA, reaching plasma concentrations of~200 μM, 13 while propionate concentrations are~10-fold lower, 2 and these are the two SCFAs that are used most commonly for experimental studies. They can couple to both inhibitory and stimulatory signalling through activation of FFAR2 and/or FFAR3, which differ in their downstream signalling cascades.…”