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The type 2 deiodinase (D2) converts the pro-hormone T4 to the metabolically active molecule T3, but its global inactivation (GLOB-D2KO) unexpectedly lowers the respiratory exchange rate (RQ) and increases food intake. Here we used FloxD2 mice to generate systemically euthyroid FAT-specific (Fabp4-Cre), ASTROCYTE-specific (GFAP-Cre) or SKELETAL MUSCLE-specific (MLC-Cre) D2KO mice that were monitored continuously. The ASTRO-D2KO mice also exhibited lower diurnal RQ and greater contribution of fatty acid oxidation to EE, but no differences in food intake were observed. In contrast, the FAT-D2KO mouse exhibited sustained (24 h) increase in RQ values, increased food intake, tolerance to glucose and sensitivity to insu-lin, all supporting greater contribution of carbohydrate oxidation to EE. Furthermore, FAT-D2KO animals that were kept on a high-fat diet for 8 weeks gained more body weight and fat, indicating impaired brown adipose tissue (BAT) thermogenesis and/or inability to oxidize the fat excess. Acclimatization of FAT-D2KO mice at thermoneutrality dissipated both features of thi