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 oth- erwise euthyroid animal. In the present studies, cold exposure increased Dio2 / BAT sympathetic stimula- tion 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 coactivator 1, in- creased 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 -methyl-substituted – -dicar- boxylic acids of C14–C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrener- gic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hy- peradrenergic stimulation prevents the otherwise nor- mal 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.
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, and Antonio C. Bianco. Endocrinology. March, 2004.