Article

Adipogenesis is differentially impaired by thyroid hormone receptor mutant isoforms.

Laboratory of Molecular Biology, Center for Cancer Research, NCI Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 37, Convent Drive, Room No. 5128, Bethesda, Maryland 20892-4264, USA.
Journal of Molecular Endocrinology (impact factor: 3.48). 04/2010; 44(4):247-55. DOI:10.1677/JME-09-0137 pp.247-55
Source: PubMed

ABSTRACT To understand the roles of thyroid hormone receptors (TRs) in adipogenesis, we adopted a loss-of-function approach. We generated 3T3-L1 cells stably expressing either TRalpha1 mutant (TRalpha1PV) or TRbeta1 mutant (TRbeta1PV). TRalpha1PV and TRbeta1PV are dominant negative mutations with a frameshift in the C-terminal amino acids. In control cells, the thyroid hormone, tri-iodothyronine (T(3)), induced a 2.5-fold increase in adipogenesis in 3T3-L1 cells, as demonstrated by increased lipid droplets. This increase was mediated by T(3)-induced expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha), which are master regulators of adipogenesis at both the mRNA and protein levels. In 3T3-L1 cells stably expressing TRalpha1PV (L1-alpha1PV cells) or TRbeta1PV (L1-beta1PV cells), adipogenesis was reduced 94 or 54% respectively, indicative of differential inhibitory activity of mutant TR isoforms. Concordantly, the expression of PPARgamma and C/EBPalpha at the mRNA and protein levels was more repressed in L1-alpha1PV cells than in L1-beta1PV cells. In addition, the expression of PPARgamma downstream target genes involved in fatty acid synthesis - the lipoprotein lipase (Lpl) and aP2 involved in adipogenesis - was more inhibited by TRalpha1PV than by TRbeta1PV. Chromatin immunoprecipitation assays showed that TRalpha1PV was more avidly recruited than TRbeta1PV to the promoter to preferentially block the expression of the C/ebpalpha gene. Taken together, these data indicate that impaired adipogenesis by mutant TR is isoform dependent. The finding that induction of adipogenesis is differentially regulated by TR isoforms suggests that TR isoform-specific ligands could be designed for therapeutic intervention for lipid abnormalities.

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Keywords

3T3-L1 cells stably
 
avidly recruited
 
C-terminal amino acids
 
CCAAT/enhancer-binding protein alpha
 
Chromatin immunoprecipitation assays
 
differential inhibitory activity
 
fatty acid synthesis
 
lipid abnormalities
 
lipoprotein lipase
 
mutant TR
 
mutant TR isoforms
 
peroxisome proliferator-activated receptor gamma
 
PPARgamma downstream target genes
 
preferentially block
 
protein levels
 
T(3)-induced expression
 
thyroid hormone receptors
 
TR isoform-specific ligands
 
TR isoforms
 
TRalpha1PV
 

Alok Mishra