Intermittent Fasting Improves Insulin Resistance by Modulating the Gut Microbiota and Bile Acid Metabolism in Diet-Induced Obesity

Abstract

Scope: Adipose tissue macrophages (ATMs) are crucial in the pathogenesis of insulin resistance (IR). Intermittent fasting (IF) is an effective intervention for obesity. However, the underlying mechanism by which IF improves IR remains unclear.

Methods and results: Male C57BL/6J mice are fed chow-diet and high-fat diet (HFD) for 12 weeks, then is randomized into ad libitum feeding or every other day fasting for 8 weeks. Markers of ATMs and expression of uncoupling protein 1 (UCP-1) are determined. Gut microbiota and bile acids (BAs) are profiled using 16S rRNA sequencing and targeted metabolomics analysis. Results indicate that IF improves IR in HFD-induced obesity. IF decreases ATM infiltration, pro-inflammatory M1 gene expression, and promotes white adipose tissue (WAT) browning by elevating UCP-1 expression. IF restructures microbiota composition, significantly expanding the abundance of Verrucomicrobia particularly Akkermansia muciniphila, with the decrease of that of Firmicutes. IF increases the level of total BAs and alters the composition of BAs with higher proportion of 12α-hydroxylated (12α-OH) BAs. The changes in these BAs are correlated with differential bacteria.

Conclusion: The findings indicate that IF improves IR partially mediated by the interplay between restructured gut microbiota and BAs metabolism, which has implications for the dietary management in obesity.

Keywords: bile acid; gut microbiota; insulin resistance; intermittent fasting; obesity.