The Role of Vagal Free Fatty Acid Receptor 3 (FFAR3) in FMT Improvement of Glucose Homeostasis

Abstract

More than 100 million Americans are obese, representing over 35% of the Unites States population. Western diet (WD) is a major cause of the obesity epidemic, and it increases prevalence of many other comorbidities, particularly Type II Diabetes. The western diet consisting of high saturated fat, high cholesterol, high sugar, and heavily processed foods robustly disrupts the composition of the gut bacteria. The microbiome ferments non‐digestible fibers to release short chain fatty acids (SCFA's) which serve as major energy substrates as well as potent signaling molecules through free fatty acid receptors 2 (FFAR2) and 3 (FFAR3). Gut dysbiosis has been associated with changes in SCFA levels that correlate with obesity in humans and mice. The SCFA's propionate and butyrate bind FFAR3 with high affinity, and FFAR3 signaling has been shown to modulate energy expenditure through sympathetic nervous system activation. The role of FFAR3 in the parasympathetic nervous system control of glucose homeostasis is currently unexplored. The vagus nerve primarily consists of sensory afferents which relay specific nutrient information from the periphery to the brain. Several studies have shown that disruption of the vagus nerve eliminates effects of the microbiome and SCFA's altering metabolism, yet the molecular mechanisms of this communication remain largely unknown. We have found that western diet alters SCFA profiles, which have been shown to modulate glucose homoeostasis and energy expenditure in a vagus nerve dependent manner. Furthermore, FFAR3 expression was reduced in the cell bodies of the vagus nerve after WD feeding. We confirmed previous findings that fecal microbiome transplantation (FMT) from lean mice reversed some WD‐induced changes to bacterial composition, plasma SCFA's, and glucose homeostasis. Our data suggest that altered FFAR3 signaling in vagal afferent neurons may contribute to some of the metabolic changes seen upon western diet feeding, and that gut microbes transplanted from lean to obese mice may improve glucose homeostasis through SCFA's binding FFAR3 in the vagus nerve.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.