Brd2 disruption in mice causes severe obesity without Type 2 diabetes
Open accessAbstract
Certain human subpopulations are metabolically healthy but obese, or metabolically obese but normal weight; such mutations uncouple obesity from glucose intolerance, revealing pathways implicated in Type 2 diabetes. Current searches for relevant genes consume significant effort. We have reported previously a novel double bromodomain protein called Brd2, which is a transcriptional co-activator/co-repressor with SWI/SNF (switch mating type/sucrose non-fermenting)-like functions that regulates chromatin. In the present study, we show that wholebody disruption of Brd2, an unusual MHC gene, causes lifelong severe obesity in mice with pancreatic islet expansion, hyperinsulinaemia, hepatosteatosis and elevated pro-inflammatory cytokines, but, surprisingly, enhanced glucose tolerance, elevated adiponectin, increased weight of brown adipose tissue, heat production and expression of mitochondrial uncoupling proteins in brown adipose tissue, reduced macrophage infiltration in white adipose tissue, and lowered blood glucose, leading to an improved metabolic profile and avoiding eventual Type 2 diabetes. Brd2 is highly expressed in pancreatic β-cells, where it normally inhibits β-cell mitosis and insulin transcription. In 3T3-L1 pre-adipocytes, Brd2 normally co-represses PPAR-γ (peroxisome-proliferator-activated receptor-γ) and inhibits adipogenesis. Brd2 knockdown protects 3T3-L1 adipocytes from TNF-α (tumour necrosis factor-α)-induced insulin resistance, thereby decoupling inflammation from insulin resistance. Thus hypomorphic Brd2 shifts energy balance toward storage without causing glucose intolerance and may provide a novel model for obese metabolically healthy humans.
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Simultaneous degradation of the three BRD proteins may increase drug toxicities.
“However, simultaneous degradation of the three BRD proteins may increase drug toxicities [100–102].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [102]
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- Authors
- Wang, F., Liu, H., Blanton, W. P., Belkina, A., Lebrasseur, N. K., & Denis, G. V.
- Affiliations
- Boston University (US)
- Corresponding author
- Wang, Fangnian
- Liu, Hongsheng
- Belkina, Anna
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2009-12-14
- Volume
- 425
- Issue
- 1
- Pages
- 71-85
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC2819394
- OpenAlex
- W2150727212
- Cited by
- 185
- References
- 59
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 11 · 2023: 4 · 2022: 13 · 2021: 14 · 2020: 13 · 2019: 9 · 2018: 8 · 2017: 18 · 2016: 18 · 2015: 16 · 2014: 14 · 2013: 12 · 2012: 12
- FWCI
- 6.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R29CA075107)
- National Institute of Allergy and Infectious Diseases (T32AI007309)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, P30DK046200, R01DK056690)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- BRD2, bromodomain proteins, obesity, type 2 diabetes, metabolically healthy obesity, pancreatic beta cells, brown adipose tissue, mitochondrial uncoupling, insulin resistance, adipogenesis, PPARγ, inflammation, adiponectin, hepatic steatosis, corepressors, 3T3-L1 adipocytes, TNF-α
- MeSH terms
- Bromodomain Containing Proteins, Animals, Blood Glucose, Cell Differentiation, Cell Line, Chromosomal Proteins, Non-Histone, Diabetes Mellitus, Type 2, Fasting, Humans, Insulin, Insulin Resistance, Macrophages, Mice, Inbred C57BL, Obesity, Severity of Illness Index, Transcription Factors, Gene Expression, Cytokines, Protein Serine-Threonine Kinases, Adipocytes, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Leptin, 3T3-L1 Cells, Cell Line, Tumor, PPAR gamma, Mice, Adiponectin
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