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Molecular and Cellular Biology, March 2007, p. 2359-2371, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.02189-06

Impaired Adipogenesis Caused by a Mutated Thyroid Hormone {alpha}1 Receptor{triangledown}

Hao Ying, Osamu Araki, Fumihiko Furuya, Yasuhito Kato, and Sheue-Yann Cheng*

Laboratory of Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892

Received 22 November 2006/ Accepted 2 January 2007

Thyroid hormone (T3) is critical for growth, differentiation, and maintenance of metabolic homeostasis. Mice with a knock-in mutation in the thyroid hormone receptor {alpha} gene (TR{alpha}1PV) were created previously to explore the roles of mutated TR{alpha}1 in vivo. TR{alpha}1PV is a dominant negative mutant with a frameshift mutation in the carboxyl-terminal 14 amino acids that results in the loss of T3 binding and transcription capacity. Homozygous knock-in TR{alpha}1PV/PV mice are embryonic lethal, and heterozygous TR{alpha}1PV/+ mice display the striking phenotype of dwarfism. These mutant mice provide a valuable tool for identifying the defects that contribute to dwarfism. Here we show that white adipose tissue (WAT) mass was markedly reduced in TR{alpha}1PV/+ mice. The expression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), the key regulator of adipogenesis, was repressed at both mRNA and protein levels in WAT of TR{alpha}1PV/+ mice. Moreover, TR{alpha}1PV acted to inhibit the transcription activity of PPAR{gamma} by competition with PPAR{gamma} for binding to PPAR{gamma} response elements and for heterodimerization with the retinoid X receptors. The expression of TR{alpha}1PV blocked the T3-dependent adipogenesis of 3T3-L1 cells and repressed the expression of PPAR{gamma}. Thus, mutations of TR{alpha}1 severely affect adipogenesis via cross talk with PPAR{gamma} signaling. The present study suggests that defects in adipogenesis could contribute to the phenotypic manifestation of reduced body weight in TR{alpha}1PV/+ mice.

* Corresponding author. Mailing address: Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Dr., Room 5128, Bethesda, MD 20892-4264. Phone: (301) 496-4280. Fax: (301) 402-1344. E-mail: chengs{at}mail.nih.gov.

{triangledown} Published ahead of print on 12 January 2007.

Molecular and Cellular Biology, March 2007, p. 2359-2371, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.02189-06






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