Regulation of Energy Balance by a Gut-Brain Axis Mediated by SCFAs and FFA2/3 in the Brain

Short-chain fatty acids (SCFAs) derived from gut microbiota fermentation have been shown to generate beneficial metabolic effects on energy and glucose homeostasis by binding with free fatty acid receptors 2 (FFA2) and 3 (FFA3). Accumulating evidence indicates that the gut microbiota/SCFAs interact with the central nervous system (CNS) to regulate central metabolic function. Interestingly, we found that a single bolus intracerebroventricular (ICV) injection of acetate (ACE), propionate (PRO), or butyrate (BUT) dose-dependently inhibited food intake in an FFA2/3-dependent manner. Notably, both in situ hybridization and RNAscope analysis showed that FFA3 but not FFA2 was expressed in the cerebellar granule neurons, which was inhibited by PRO or FFA3-selective agonists in a Gi/o-dependent mechanism. We also showed that high-fat diet (HFD)-induced hypothalamic inflammation is diminished by dietary fiber supplementation, which is associated with increased circulating SCFAs. Notably, these anti-inflammatory effects of dietary fiber supplementation were partially attenuated in FFA2/3 double-knockout mice, suggesting a beneficial effect of FFA2/3 on hypothalamic inflammation. Taking all these together, our results suggest a model that SCFAs act on the brain to regulate energy homeostasis and hypothalamic inflammation. Disclosure X.Yang: None. P.Xu: None. P.Luo: None. B.Feng: None. H.Ye: None. N.Antony: None. L.Carrillo-sáenz: None. V.C.Torres irizarry: None. B.T.Layden: Consultant; Bayer Inc. Y.He: None. Funding National Institutes of Health (R01DK123098, P30DK020595 to P.X.), (P20GM135002, R01DK129548 to Y.H.), (T32AA026577 to V.C.T.I.); American Heart Association (915789 to V.C.T.I.), (20POST35120600 to Y.H.); U.S. Department of Defense (W81XWH-20-1-0075 to P.X