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Thyroid. 2010 May;20(5):545-53. doi: 10.1089/thy.2009.0318.

Impaired metabolic effects of a thyroid hormone receptor beta-selective agonist in a mouse model of diet-induced obesity.

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  • 1Division of Endocrinology, Diabetes, and Metabolism, Miller School of Medicine, University of Miami, Florida 33136, USA.

Abstract

BACKGROUND:

The use of selective agonists of the thyroid hormone receptor isoform beta (TRbeta) has been linked to metabolic improvement in animal models of diet-induced obesity, nonalcoholic liver disease, and genetic hypercholesterolemia.

METHODS:

To identify potential target tissues of such compounds, we exposed primary murine brown adipocytes and skeletal myocytes for 24 hours to 50 nM GC-24, a highly selective TRbeta agonist. GC-24 (17 ng/[g BW.day] for 36 days) was also tested in a mouse model of diet-induced obesity.

RESULTS:

While the brown adipocytes responded to GC-24, with 17%-400% increases in the expression of 12 metabolically relevant genes, the myocytes remained largely unresponsive to GC-24 treatment. In control mice kept on chow diet, GC-24 treatment accelerated energy expenditure by about 15% and limited body weight gain by about 50%. However, in the obese animals the GC-24-mediated reduction in body weight gain dropped to only 20%, while energy expenditure remained unaffected. In addition, an analysis of gene expression in the skeletal muscle, brown adipose tissue, and liver of these obese animals failed to identify a conclusive GC-24 transcriptome footprint.

CONCLUSION:

Feeding a high-fat diet impairs most of the beneficial metabolic effects associated with treatment with TRbeta-selective agonists.

Comment in

PMID:
20406106
[PubMed - indexed for MEDLINE]
PMCID:
PMC2941403
Free PMC Article

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