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-<p>The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study we quantified the transcriptome, a subset of the metabolome, and using targeted proteomics, a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, <em>Dhtkd1</em> was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. We further used the integrated molecular profiles to characterize complex pathways, as illustrated with the mitochondrial unfolded protein response (UPR<sup>mt</sup>). UPR<sup>mt</sup> shows strikingly variant responses at the transcript and protein level that are remarkably conserved between <em>C.elegans</em>, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes.</p>