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

• Published in: Thyroid (New York, N.Y.) Vol. 20; no. 5; p. 545
• Main Authors: Castillo, Melany, Freitas, Beatriz C G, Rosene, Matthew L, Drigo, Rafael A, Grozovsky, Renata, Maciel, Rui M B, Patti, Mary Elizabeth, Ribeiro, Miriam O, Bianco, Antonio C
• Format: Journal Article
• Language: English
• Published: United States 01.05.2010
• Subjects: Acetates - adverse effects; Acetates - therapeutic use; Adipocytes, Brown - drug effects; Adipocytes, Brown - metabolism; Animals; Anti-Obesity Agents - adverse effects; Anti-Obesity Agents - therapeutic use; Benzhydryl Compounds - adverse effects; Benzhydryl Compounds - therapeutic use; Body Weight - drug effects; Calorimetry, Indirect; Cells, Cultured; Diet; Energy Metabolism - drug effects; Gene Expression - drug effects; Male; Metabolism - drug effects; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Obesity - drug therapy; Organ Size - drug effects; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Thyroid Hormone Receptors beta - agonists; Triiodothyronine - pharmacology
• ISSN: 1557-9077
• DOI: 10.1089/thy.2009.0318

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