Mice with Targeted Disruption of the Dio2 Gene Have Cold-Induced Overexpression of the Uncoupling Protein 1 Gene but Fail to Increase Brown Adipose Tissue Lipogenesis and Adaptive Thermogenesis

Marcelo A. Christoffolete, Camila C.G. Linardi, Lucia De Jesus, Katia Naomi Ebina, Suzy D. Carvalho, Miriam O. Ribeiro, Rogerio Rabelo, Cyntia Curcio, Luciane Martins, Edna T. Kimura, Antonio C. Bianco

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3′,5-triiodothyronine (T3), the disruption of which (Dio2 -/-) results in brown adipose tissue (BAT)-specific hypothyroidism in an otherwise euthyroid animal. In the present studies, cold exposure increased Dio2-/- BAT sympathetic stimulation ∼10-fold (normal ∼4-fold); as a result, lipolysis, as well as the mRNA levels of uncoupling protein 1, guanosine monophosphate reductase, and peroxisome proliferator-activated receptor y coactivator 1, increased well above the levels detected in the cold-exposed wild-type animals. The sustained Dio2 -/- BAT adrenergic hyperresponse suppressed the three- to fourfold stimulation of BAT lipogenesis normally seen after 24-48 h in the cold. Pharmacological suppression of lipogenesis with ββ′ -methyl-substituted α-ω-dicarboxylic acids of C14-C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrenergic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hyperadrenergic stimulation prevents the otherwise normal stimulation in BAT lipogenesis during cold exposure, rapidly exhausting the availability of fatty acids. The latter is the preponderant determinant of the impaired adaptive thermogenesis and hypothermia in cold-exposed Dio2-/- mice.

Original languageEnglish (US)
Pages (from-to)577-584
Number of pages8
JournalDiabetes
Volume53
Issue number3
DOIs
StatePublished - Mar 2004

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Christoffolete, M. A., Linardi, C. C. G., De Jesus, L., Ebina, K. N., Carvalho, S. D., Ribeiro, M. O., Rabelo, R., Curcio, C., Martins, L., Kimura, E. T., & Bianco, A. C. (2004). Mice with Targeted Disruption of the Dio2 Gene Have Cold-Induced Overexpression of the Uncoupling Protein 1 Gene but Fail to Increase Brown Adipose Tissue Lipogenesis and Adaptive Thermogenesis. Diabetes, 53(3), 577-584. https://doi.org/10.2337/diabetes.53.3.577