Background: The use of selective agonists of the thyroid hormone receptor isoform b (TRb) has been linked to metabolic improvement in animal models of diet-induced obesity, nonalcoholic liver disease, and genetic hy- percholesterolemia.
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 TRb agonist. GC-24 (17 ng=[g BWday] 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 TRb-selective agonists.
Impaired Metabolic Effects of a Thyroid Hormone Receptor Beta-Selective Agonist in a Mouse Model of Diet-Induced Obesity.
Melany Castillo, Beatriz C.G. Freitas, Matthew L. Rosene, Rafael A. Drigo, Renata Grozovsky, Rui M.B. Maciel, Mary Elizabeth Patti, Miriam O. Ribeiro, and Antonio C. Bianco. Thyroid, 2010; doi:10.1089=thy.2009.0318