FRI013 Free Fatty Acid Receptors 2 And 3 Mediate The Beneficial Effects Of Fiber

Abstract

Abstract Disclosure: N.S. Pandya: None. M. Priyadarshini: None. B.T. Layden: None. The Gut Microbiome (GM) is a key player in whole body metabolism. Microbial dysregulation and dysbiosis have been linked to multiple pathologies including obesity and type 2 diabetes. Microbes influence host function by releasing various metabolites when interacting with ingested materials. Key metabolites include short chain fatty acids (SCFAs) produced through microbial fermentation of fiber. Fiber intake is known to increase GM diversity; this process has been suggested to protect against obesity and type 2 diabetes. While SCFAs have been implicated in this process, the overall mechanism is still unclear. Free fatty acid receptors 2 and 3 (FFA2 and FFA3) occupy a unique position through which the GM can exert an effect on host metabolism. These G-protein coupled receptors are known to sense SCFAs and can modulate the subsequent secretion of incretin and insulin hormones thus regulating host appetite and blood-glucose control. FFA2 and FFA3 are expressed in many tissues, including adipocytes, neurons, and most importantly, intestinal enteroendocrine L cells and pancreatic β cells. For this reason, complete understanding of their function is necessary, and elucidating their signaling mechanisms may have significant therapeutic value in the treatment of the obesity epidemic and diabetes. Here, we seek to understand the whole-body impact of the gut microbiota-SCFA-FFA2/3 axis in the metabolically protective role of fiber. We used here a novel whole-body FFA2/FFA3 double knockout (F2,3-dKO) mouse model to obtain a holistic understanding of SCFA sensing mechanisms when mice are fed obesogenic diets supplemented with or without fermentable fiber. Double knockout mice, alongside matched wild-type controls were challenged with either a high fat western diet (WD), or WD supplemented with 20% fructooligosaccharides (FOS), a fermentable fiber (WD + 20% FOS). Preliminary data showed a significant rise in body weight, fat mass, and insulin resistance in WD fed F2,3-dKO mice alongside matched wild-type controls. Wild-type mice, when challenged with WD supplemented with fiber, were protected from this effect with only a mild increase in body weight and insulin resistance. Interestingly, F2,3-dKO mice, fed WD + 20% FOS were insensitive to fiber induced metabolic benefits. This suggests that FFA2 and FFA3 are essential for fermentable fiber mediated metabolic benefits against WD induced obesity. Further studies are now aimed to understand the mechanism behind this protective effect. Presentation: Friday, June 16, 2023