TY - JOUR
T1 - Impaired metabolic effects of a thyroid hormone receptor beta-selective agonist in a mouse model of diet-induced obesity
AU - Castillo, Melany
AU - Freitas, Beatriz C.G.
AU - Rosene, Matthew L.
AU - Drigo, Rafael A.
AU - Grozovsky, Renata
AU - MacIel, Rui M.B.
AU - Patti, Mary Elizabeth
AU - Ribeiro, Miriam O.
AU - Bianco, Antonio C.
PY - 2010/5/1
Y1 - 2010/5/1
N2 - Background: The use of selective agonists of the thyroid hormone receptor isoform β (TRβ) 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 TRβ 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 TRβ-selective agonists.
AB - Background: The use of selective agonists of the thyroid hormone receptor isoform β (TRβ) 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 TRβ 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 TRβ-selective agonists.
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U2 - 10.1089/thy.2009.0318
DO - 10.1089/thy.2009.0318
M3 - Article
C2 - 20406106
AN - SCOPUS:77952325654
SN - 1050-7256
VL - 20
SP - 545
EP - 553
JO - Thyroid
JF - Thyroid
IS - 5
ER -