The role of in cellular metabolism is not fully characterized and what we do understand has been primarily demonstrated in vitro. Our studies aimed to characterize the role of in metabolic pathways in a whole body system. In vivo studies using C57BL/6 wild-type and transgenic humanized mice demonstrate the effect of human on the whole body metabolic phenotype and start to elucidate the mechanism by which this occurs. Promethion metabolic chambers and glucose tolerance tests measured a number of metabolic outputs of male and female mice that were either wild-type (normal mouse gene) or humanized mice (knockout /knock-in human gene). Humanized mice are more lean, hyperactive, display higher energy expenditure, and demonstrate a sexual dimorphism in lean mass and glucose tolerance when compared with wild-type mice on the same genetic background. To begin to elucidate the mechanisms behind the observed metabolic phenotype, we performed mass spectrometry, SuperArray, and Western blot analysis using skeletal muscle, a metabolic organ that significantly impacts energy metabolism. Proteomic and genomic analysis revealed changes in a number of metabolic pathways that may be implicated in the observed whole body metabolic phenotype. We concluded that substituting for in an in vivo model altered the overall metabolic profile of humanized mice. Thus, the gene appears to have a significant impact on metabolic pathways, and these effects differ from mouse to human. This is the first in vivo evidence demonstrating the complex effects of expression in whole body metabolism.