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


CONCLUSIONS
Feeding a high-fat diet impairs most of the beneficial metabolic effects associated with treatment with TRbeta-selective agonists.
Castillo
Melany
M
Division of Endocrinology, Diabetes, and Metabolism, Miller School of Medicine, University of Miami, Florida 33136, USA.
Freitas
Beatriz C G
BC
Rosene
Matthew L
ML
Drigo
Rafael A
RA
Grozovsky
Renata
R
Maciel
Rui M B
RM
Patti
Mary Elizabeth
ME
Ribeiro
Miriam O
MO
Bianco
Antonio C
AC
D000085:Acetates / Q000009:adverse effects* / Q000627:therapeutic use*; D052437:Adipocytes, Brown / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D001559:Benzhydryl Compounds / Q000009:adverse effects* / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002153:Calorimetry, Indirect; D002478:Cells, Cultured; D004032:Diet; D004734:Energy Metabolism / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D008660:Metabolism / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy*; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*; D014284:Triiodothyronine / Q000494:pharmacology
D000085:Acetates; D019440:Anti-Obesity Agents; D001559:Benzhydryl Compounds; C483767:GC 24 compound; D012333:RNA, Messenger; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine
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