Central and peripheral regulations mediated by short-chain fatty acids on energy homeostasis

The human gut microbiota influences obesity, insulin resistance, and the subsequent development of type 2 diabetes (T2D). The gut microbiota digests and ferments nutrients resulting in the production of short-chain fatty acids (SCFAs), which generate various beneficial metabolic effects on energy and glucose homeostasis. However, their roles in the central nervous system (CNS)-mediated outputs on the metabolism have only been minimally studied. Here, we explore what is known and future directions that may be worth exploring in this emerging area. Specifically, we searched studies or data in English by using PubMed, Google Scholar, and the Human Metabolome Database. Studies were filtered by time from 1978 to March 2022. As a result, 195 studies, 53 reviews, 1 website, and 1 book were included. One hundred and sixty-five of 195 studies describe the production and metabolism of SCFAs or the effects of SCFAs on energy homeostasis, glucose balance, and mental diseases through the gut-brain axis or directly by a central pathway. Thirty of 195 studies show that inappropriate metabolism and excessive of SCFAs are metabolically detrimental. Most studies suggest that SCFAs exert beneficial metabolic effects by acting as the energy substrate in the TCA cycle, regulating the hormones related to satiety regulation and insulin secretion, and modulating immune cells and microglia. These functions have been linked with AMPK signaling, GPCRs-dependent pathways, and inhibition of histone deacetylases (HDACs). However, the studies focusing on the central effects of SCFAs are still limited. The mechanisms by which central SCFAs regulate appetite, energy expenditure, and blood glucose during different physiological conditions warrant further investigation.