The worldwide prevalence of obesity-associated pathologies, including type 2 
diabetes, requires thorough investigation of mechanisms and interventions. 
Recent studies have highlighted thyroid hormone analogs and derivatives as 
potential agents able to counteract such pathologies. In this study, in rats 
receiving a high-fat diet (HFD), we analyzed the effects of a 4-wk daily 
administration of a naturally occurring iodothyronine, 3,5-diiodo-L-thyronine 
(T2), on the gastrocnemius muscle metabolic/structural phenotype and insulin 
signaling. The HFD-induced increases in muscle levels of fatty acid translocase 
(3-fold; P<0.05) and TGs (2-fold, P<0.05) were prevented by T2 (each; P<0.05 vs. 
HFD). T2 increased insulin-stimulated Akt phosphorylation levels (∼2.5-fold; 
P<0.05 vs. HFD). T2 induced these effects while sparing muscle mass and without 
cardiac hypertrophy. T2 increased the muscle contents of fast/glycolytic fibers 
(2-fold; P<0.05 vs. HFD) and sarcolemmal glucose transporter 4 (3-fold; P<0.05 
vs. HFD). Adipocyte differentiation-related protein was predominantly present 
within the slow/oxidative fibers in HFD-T2. In T2-treated rats (vs. HFD), 
glycolytic enzymes and associated components were up-regulated (proteomic 
analysis, significance limit: 2-fold; P<0.05), as was phosphofructokinase 
activity (by 1.3-fold; P<0.05), supporting the metabolic shift toward a more 
glycolytic phenotype. These results highlight T2 as a potential therapeutic 
approach to the treatment of diet-induced metabolic dysfunctions.