SIRT1 and Insulin resistance: Lastly, consistent with the fact that F-K1057 and F-K1079 underlie insulin resistance, a high-fat diet, an established risk factor of insulin resistance31, increased circulating phenylalanine levels (Supplementary Fig. 7d), decreased SIRT1 levels (Supplementary Fig. 7e) as reported32,33, but had negligible effects on FARSA levels, consistently induced K1057/F-K1079 levels, and inhibited insulin signaling in the liver, muscle, and adipose tissues of mice (Supplementary Fig. 7e).