Isoleucine-restricted diets improve high-fat diet-induced nonalcoholic fatty liver disease via regulating insulin resistance and gut microbiota

Obesity, caused $\dot{V}$ by a long-term high-fat diet, is a risk factor for insulin resistance and nonalcoholic fatty liver disease (NAFLD). The gut microbiota plays an important role in NAFLD development by producing lipopolysaccharides (LPS). Isoleucine (ILE), as one of the branched-chain amino acids (BCAAs), has a negative effect on glucose and lipid metabolism in obese mice. Therefore, we speculated that isoleucine-restricted diets could prevent high-fat diet-induced insulin resistance and NAFLD. For this purpose, 30 C57BL/6J mice received a control check diet (CK), a high-fat diet (HFD), and a isoleucine-restricted diet (IR) for 12 weeks, respectively. The current study revealed that IR diets reversed HFD-induced weight gain, increased fasting glucose levels, and lipid metabolism disorder. Furthermore, IR diets attenuated HFD-induced hepatic inflammation by regulating the LPS/TLR4/NF-κB signaling pathway. Moreover, hepatic insulin resistance and gluconeogenesis disorder were significantly improved by IR diets. In addition, IR diets reshaped HFD-induced gut microbiota imbalance, reflected in decreasing the proportion of Proteobacteria phylum and LPS contents. Taken together, our studies support that restricting isoleucine in high-fat diets was a novel means of preventing obesity-induced NAFLD and insulin resistance.