Y 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 direc-tions 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 Metabo-lome 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 detrimen-tal. 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 reg-ulation 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 cen-tral effects of SCFAs are still limited. The mechanisms by which central SCFAs regulate appetite, energy expenditure, and blood glucose during different physiological con-ditions warrant further investigation. (Translational Research 2022; 248:128-150)

Automated summary

The human gut microbiota plays a role in obesity, insulin resistance, and the development of type 2 diabetes. Short-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial effects on energy and glucose metabolism. However, the understanding of their involvement in the central nervous system-mediated regulation of metabolism is still limited.