The global epidemic of dyslipidemia and its complications demands more accessible interventions. Although several therapeutic approaches have been formulated their use is limited mainly because only stringent goals are achieved. Recent reports indicated thyroid hormone (T3) analogues as new drugs to improve outcomes in dyslipidemic patients. However, the development of some of them was discontinued due their adverse cardiac and bone-related effects. 3,5-diiodo-L-thyronine (T2), a natural iodothyronine, as compared with T3, has a much lower affinity for the T3 b-receptors, which mediated the lipid-lowering actions of T3, as well as for the T3 a-receptor in the heart, thus is devoid of adverse T3-attributed effects. T2 is able either to prevent or counteract adiposity when administered to rats receiving a high-fat diet (HFD) in which an increase in hepatic fatty acid oxidation and decrease in serum cholesterol and triglycerides occur. In the liver, T2 directly activates sirtuin1, thus upregulating genes involved in mitochondrial biogenesis and downregulating lipogenic ones. These actions ultimately reduce the amount of lipids available to skeletal muscle, thus counteracting the HFD-induced insulin resistance. Moreover, T2 shifts muscle fibers toward a glycolitic phenotype, thus increasing glucose uptake and oxidation without inducing mitochondrial damage. These results open new perspectives on the use of T2 in a novel therapeutic approach as a lipid lowering agent.