Methionine restriction alleviates high-fat diet-induced obesity: Involvement of diurnal metabolism of lipids and bile acids

Circadian misalignment induced by a high-fat diet (HFD) increases the risk of metabolic diseases. Methionine restriction (MR) is known to have the potential of alleviating obesity by improving insulin sensitivity. However, the role of the circadian clock in mediating the effects of MR on obesity-related metabolic disorders remains unclear. Ten-week-old male C57BL/6 J mice were fed with a low-fat diet (LFD) or a HFD for 4 wk., followed with a full diet (0.86% methionine, w / w ) or a methionine-restricted diet (0.17% methionine, w / w ) for 8 wk. Our results showed that MR attenuated insulin resistance triggered by HFD, especially at ZT12. Moreover, MR led to a time-specific enhancement of the expression of FGF21 and activated the AMPK/PGC-1α signaling. Notably, MR upregulated the cyclical levels of cholic acid (CA) and chenodeoxycholic acid (CDCA), and downregulated the cyclical level of deoxycholic acid (DCA) in the dark phase. MR restored the HFD-disrupted cyclical fluctuations of lipidolysis genes and BAs synthetic genes and improved the circulating lipid profile. Also, MR improved the expressions of clock-controlled genes (CCGs) in the liver and the brown adipose tissue throughout one day. In conclusion, MR exhibited the lipid-lowering effects on HFD-induced obesity and restored the diurnal metabolism of lipids and BAs, which could be partly explained by improving the expression of CCGs. These findings suggested that MR could be a potential nutritional intervention for attenuating obesity-induced metabolic misalignment. Methionine restriction led to time-specific improvement in insulin sensitivity, enhanced diurnal expressions of FGF21 and clock-controlled genes, and restored cyclical metabolism of lipids and bile acids in high-fat diet-fed mice. • MR led to time-specific improvement of insulin sensitivity. • MR enhanced the diurnal expression of FGF21 and inhibited lipid accumulation. • MR restored the cyclical fluctuations of the metabolism of lipids and BAs in obese mice. • MR improved the expressions of CCGs in the liver and the BAT.