Food intake regulates energy balance, and its dysregulation leads to metabolic disorders such as obesity and diabetes. Free fatty acids are not only essential nutrients but also act as signaling molecules in various cellular processes. Recent studies have shown that the receptors GPR40, GPR41, GPR43, and GPR120 are new drug targets for treating metabolic disorders because they are activated by free fatty acids. Two of these receptors, GPR41 and GPR43, are activated by short-chain fatty acids (SCFAs: acetate, propionate, and butyrate), which are important energy sources for the host. During feeding, SCFAs are produced by the microbial fermentation of dietary fiber in the gut. The gut microbiota affect nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. Hence, GPR41 and GPR43 are also a focus of research into energy regulation via SCFAs. We report that these SCFA receptors are involved in energy homeostasis: GPR41 regulates sympathetic activity, and GPR43 regulates adipose-insulin signaling by sensing SCFAs produced by gut microbiota. We believe that these results will provide valuable insight into therapeutic targets for treating metabolic disorders and diabetes, as well as in the use of probiotics to control gut microbiota.