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Mice with Targeted Disruption of the Dio2 Gene Have Cold-Induced Overexpression of the Uncoupling Protein 1 Gene but Fail to Increase Brown Adipose Tissue Lipogenesis and Adaptive Thermogenesis
Open accessAbstract
The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3′,5-triiodothyronine (T3), the disruption of which (Dio2−/−) results in brown adipose tissue (BAT)-specific hypothyroidism in an otherwise euthyroid animal. In the present studies, cold exposure increased Dio2−/− BAT sympathetic stimulation ∼10-fold (normal ∼4-fold); as a result, lipolysis, as well as the mRNA levels of uncoupling protein 1, guanosine monophosphate reductase, and peroxisome proliferator–activated receptor γ coactivator 1, increased well above the levels detected in the cold-exposed wild-type animals. The sustained Dio2−/− BAT adrenergic hyperresponse suppressed the three- to fourfold stimulation of BAT lipogenesis normally seen after 24–48 h in the cold. Pharmacological suppression of lipogenesis with ββ′-methyl-substituted α-ω-dicarboxylic acids of C14–C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrenergic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hyperadrenergic stimulation prevents the otherwise normal stimulation in BAT lipogenesis during cold exposure, rapidly exhausting the availability of fatty acids. The latter is the preponderant determinant of the impaired adaptive thermogenesis and hypothermia in cold-exposed Dio2−/− mice.
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“The relevance of thyroid hormone regulation for BAT function is illustrated by the blunted thermogenic response observed in DIO2 knockout mice, despite their increased UCP1 expression 89.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [89]
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Metadata
- Authors
- Christoffolete, M. A., Linardi, C. C. G., de Jesus, L., Ebina, K. N., Carvalho, S. D., Ribeiro, M. O., Rabelo, R., Curcio, C., Martins, L., Kimura, E. T., & Bianco, A. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Universidade de São Paulo (BR)
- Department of Medicine, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Histology & Embryology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Department of Physiology & Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
- Universidade Presbiteriana Mackenzie (BR)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2004-03-01
- Volume
- 53
- Issue
- 3
- Pages
- 577-584
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2155560632
- Cited by
- 212
- References
- 40
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 7 · 2023: 10 · 2022: 13 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 9 · 2017: 13 · 2016: 11 · 2015: 13 · 2014: 19 · 2013: 12 · 2012: 6
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Thyroid Association
- Fundação de Amparo à Pesquisa do Estado de São Paulo (97/13888-5)
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK36256, R01DK036256)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- DIO2, type 2 deiodinase, brown adipose tissue, adaptive thermogenesis, UCP1, lipogenesis, cold exposure, sympathetic nervous system, hypothyroidism, thyroxine, fatty acid availability, hypothermia
- MeSH terms
- Uncoupling Protein 1, Iodothyronine Deiodinase Type II, Animals, Base Sequence, Body Temperature Regulation, Adipose Tissue, Brown, Carrier Proteins, Gene Expression Regulation, Hypothyroidism, Iodide Peroxidase, Ion Channels, Lipids, Membrane Proteins, Transcription Factors, Polymerase Chain Reaction, DNA Primers, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Mitochondrial Proteins, Mice
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