Impaired Metabolic Effects of a Thyroid Hormone Receptor Beta-Selective Agonist in a Mouse Model of Diet-Induced Obesity
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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.
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A high-fat diet can reduce expression of transcriptional regulators necessary for T3 signaling in the liver.
“For example, there is considerable evidence that a high-fat diet can reduce the expression of transcriptional regulators that are necessary for T3 signaling in the liver (73–75).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [75]
The Discussion (page unavailable) reports impaired thyroid-hormone signaling in the liver of high-fat-fed mice and suggests that reduced levels of Pgc-1, a TR coactivator, might explain it. It calls that mechanism unknown, however, and does not establish reduced expression of multiple transcriptional regulators necessary for T3 signaling. (LLM, conf=0.84)
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- Authors
- Castillo, M., Freitas, B. C. G., Rosene, M. L., Drigo, R. A., Grozovsky, R., Maciel, R. M. B., Patti, M. E., Ribeiro, M. O., & Bianco, A. C.
- Affiliations
- University of Miami (US)
- Universidade Federal de São Paulo (BR)
- Joslin Diabetes Center (US)
- Universidade Presbiteriana Mackenzie (BR)
- Corresponding author
- Bianco, Antonio C.
- Venue
- Thyroid
- Publisher
- SAGE Publications
- Published
- 2010-05
- Volume
- 20
- Issue
- 5
- Pages
- 545-553
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- PMC
- PMC2941403
- OpenAlex
- W2081953333
- Cited by
- 28
- References
- 31
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 4 · 2013: 2
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Thyroid (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 65055, R01DK065055)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- thyroid hormone receptor beta, diet-induced obesity, high-fat diet, brown adipocytes, skeletal muscle, energy expenditure, weight gain, gene expression, metabolic effects
- MeSH terms
- Acetates, Animals, Benzhydryl Compounds, Body Weight, Calorimetry, Indirect, Cells, Cultured, Diet, Energy Metabolism, Male, Metabolism, Mice, Inbred C57BL, Obesity, Organ Size, RNA, Messenger, Triiodothyronine, Gene Expression, Muscle Fibers, Skeletal, Anti-Obesity Agents, Thyroid Hormone Receptors beta, Mice, Adipocytes, Brown
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