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

Endocrinology. 2008 Dec;149(12):6471-86. doi: 10.1210/en.2008-0718. Epub 2008 Aug 21.


Unable to activate brown adipose tissue (BAT) thermogenesis, alphaT3-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Body Weight / genetics
  • Dietary Fats / administration & dosage
  • Energy Metabolism / genetics
  • Female
  • Iodide Peroxidase / metabolism
  • Lipoprotein Lipase / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Obesity / etiology
  • Obesity / genetics*
  • Obesity / physiopathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thermogenesis / genetics*
  • Thermogenesis / physiology
  • Thyroid Hormone Receptors alpha / genetics*
  • Thyroid Hormone Receptors alpha / physiology


  • Dietary Fats
  • Thyroid Hormone Receptors alpha
  • Iodide Peroxidase
  • Lipoprotein Lipase