3,5-Diiodothyronine (3,5-T2) has been shown to exert pleiotropic beneficial effects. In this study we investigated whether 3,5-T2 prevent several energy metabolism disorders related to type 2 diabetes mellitus (T2DM) in gerbils diabetes-prone P. obesus. 157 male gerbils were randomly to Natural Diet (ND-controlled) or a HED (High-Energy Diet) divided in: HED- controlled, HED-3,5-T2 and HED- Placebo groups. 3,5-T2 has been tested at 25 µg dose and was administered under subcutaneous pellet implant during 10 weeks. Isolated hepatocytes were shortly incubated with 3,5-T2 at 10−6 M and 10−9 M dose in the presence energetic substrates. 3,5-T2 treatment reduce visceral adipose tissue, prevent the insulin resistance, attenuated hyperglycemia, dyslipidemia, and reversed liver steatosis in diabetes P. obesus. 3,5-T2 decreased gluconeogenesis, increased ketogenesis and enhanced respiration capacity. 3,5-T2 potentiates redox and phosphate potential both in cytosol and mitochondrial compartment. The use of 3,5-T2 as a natural therapeutic means to regulate cellular energy metabolism. We suggest that 3,5-T2 may help improve the deleterious course of obesity and T2DM, but cannot replace medical treatment.