Depletion of individual dietary amino acids induce distinct metabolic and chromatin states

Reducing dietary levels of protein or specific essential amino acids (EAAs) promote favorable metabolic reprogramming, including improved glucose tolerance, increased insulin sensitivity, and reduced fat mass. However, the extent to which shared or EAA-specific mechanisms facilitate diet-associated phenotypes remains unclear. Here, we compared the physiological and molecular responses to dietary levels of methionine, leucine, and isoleucine by feeding C57BL/6J mice diets in which each of these specific AAs is depleted. Dietary depletion of Met, Leu, or Ile (Met-D, Leu-D, or Ile-D) elicited distinct, AA-specific physiological and hepatic molecular (transcriptome, metabolome, histone proteome) responses that were not phenocopied by mTORC1 inhibition via rapamycin treatment. Ile-D yielded the most distinct and dramatic responses, highlighted by expression of select chromatin modifying and metabolic enzymes that led to a prominent epigenetic state of histone H2A/H4 hypoacetylation and maintained hepatic acetyl-CoA levels despite downregulated β-oxidation. Multi-omics factor analysis of 14,139 data points objectively affirmed Ile-D phenotypes are distinct from Met-D or Leu-D and identified metabolic and chromatin features as primary discriminators. We further demonstrated the metabolic and epigenetic responses to Ile-D can be recapitulated in vitro, suggesting that these responses are cell intrinsic. Together, these results demonstrate that dietary depletion of EAAs induce unique phenotypes and highlight distinct molecular mechanisms by which individual EAAs may control metabolic health.