Skeletal muscle exhibits high plasticity with respect to its metabolic properties. Recent work has shown that an increased muscle oxidative competence can improve systemic metabolism. 3,5-diiodo-L-thyronine and its functional analogue, TRC150094 (TRC) have been shown to have such a capacity when administered to rats receiving a high-fat diet (HFD). Here, combining metabolic/ structural analyses, 2D-E, MS, and BN-PAGE, we studied how the tibialis muscle phenotype of HFD-rats responds to TRC. We obtained an integrated view of the phenotypic/metabolic adaptations occurring in this muscle following TRC treatment. Interestingly, TRC strongly increased the MHCIb protein level inducing a shift toward a more oxidative phenotype. Accordingly, TRC significantly enhanced the ability of muscle mitochondria to oxidise fatty acids. Proteomic analysis revealed that the protein expression levels of the fast isotypes of myosin light chains and of troponin C2 fast decreased significantly following TRC treatment, in agreement with a shift toward the oxidative phenotype. Coherently, glycolytic enzymes (ie. a and b-enolase, triosephosphate isomerise, creatine kinase) were all down regulated by TRC. In terms of in-gel activity TRC-treatment resulted in a stimulation of mitochondrial complexes II and V. This study will help identify therapeutic target and develop pharmacological strategies to safely alleviate or reverse overweight-associated diseases.