Dietary Amino Acid Source Elicits Sex‐Specific Metabolic Response to Diet‐Induced NAFLD in Mice

Scope Non‐alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, the metabolic and hepatic effects of dietary amino acid (AA) source is assessed in Western diet (WD)‐induced NAFLD in male and female mice. Methods and results The AA source is either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein‐based WD display glucose intolerance, fasting hyperglycemia, and insulin‐resistance and develop NAFLD associated with changes in hepatic gene expression and microbiota dysbiosis. In contrast, males fed the AA‐based WD show no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein‐based WD. Females are protected against WD‐induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. Conclusions Free dietary AA intake prevents the unhealthy metabolic outcomes of a WD preferentially in male mice. The replacement of casein by a free amino acid mixture (AA), mimicking its composition, in a western‐diet (WD) prevents body weight gain in both male and female mice. Dietary free amino acids in the WD prevent hepatic damage and associated liver gene expression changes only in males. Collectively, the data show that free dietary AA intake prevents the unhealthy metabolic outcomes of a WD in a sex‐specific manner that may involve the gut microbiota.