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Mice Lacking the Thyroid Hormone Receptor- Gene Spend More Energy in Thermogenesis, Burn More Fat, and Are Less Sensitive to High-Fat Diet-Induced Obesity

Baystate Medical Center (P.P., O.S., J.E.S.), Division of Endocrinology, Diabetes and Metabolism, Pioneer Valley Life Sciences Institute, Tufts University School of Medicine, Springfield, Massachusetts, 01199; and Institut de Génomique Fonctionnelle de Lyon Unité Mixte de Recherche 5242 (K.G., J.S.), Université de Lyon; Institut Fédératif Biosciences Gerland Lyon Sud; Université Lyon 1, Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, Ecole Normale Supérieure de Lyon, F-69364 Lyon, France

Address all correspondence and requests for reprints to: J. Enrique Silva, M.D., Baystate Medical Center, Division of Endocrinology, Room S2620, 759 Chestnut Street, Springfield, Massachusetts 01199. E-mail: enrique.silva{at}bhs.org.

Unable to activate brown adipose tissue (BAT) thermogenesis, T₃-receptor-deficient mice (Thra-0/0) are cold intolerant. Our objective was to investigate the impact on energy economy and mechanisms of the alternate facultative thermogenesis developed. Energy expenditure (oxygen and food consumption) is elevated in Thra-0/0 mice reared at room temperature. Such difference disappears at thermoneutrality (30 C) and expands as ambient temperature becomes colder (P < 0.001). Despite eating more, Thra-0/0 are leaner than wild-type (WT) mice (P < 0.01), whereas these, whether on chow or high-fat diet, gained more weight (g/d: 0.12 ± 0.002 vs. 0.08 ± 0.002 and 0.25 ± 0.005 vs. 0.17 ± 0.005, respectively) and adiposity than Thra-0/0 mice (P < 0.001). The respiratory quotient was lower in Thra-0/0 than WT mice (P < 0.001), after feeding or fasted, on chow or high-fat diet, indicating a preference for fat as fuel, which was associated with increased lipoprotein lipase (LPL) expression in skeletal muscle of Thra-0/0 mice but with no differences in gene expression in white adipose tissue. Type-2 deiodinase (D2) was increased in BAT and aerobic muscle of Thra-0/0 mice. This and liver D1 were increased by a high-fat diet in both genotypes, as also were serum T₃ and T₃/T₄ ratio, but more in Thra-0/0 than WT mice (P < 0.001). Remarkably, when studied at thermoneutrality, genotype differences in weight and adiposity gain, respiratory quotient, D2, and LPL disappeared. Thus, disruption of BAT thermogenesis in Thra-0/0 mice activates an alternate facultative thermogenesis that is more energy demanding and associated with reduced fuel efficiency, leanness, increased capacity to oxidize fat, and relative resistance to diet-induced obesity, in all of which muscle LPL and deiodinases play a key role.