AMPK/α-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis
Open accessAbstract
Promoting brown adipose tissue (BAT) development is an attractive strategy for the treatment of obesity, as activated BAT dissipates energy through thermogenesis; however, the mechanisms controlling BAT formation are not fully understood. We hypothesized that as a master regulator of energy metabolism, AMP-activated protein kinase (AMPK) may play a direct role in the process and found that AMPKα1 (PRKAA1) ablation reduced Prdm16 expression and impaired BAT development. During early brown adipogenesis, the cellular levels of α-ketoglutarate (αKG), a key metabolite required for TET-mediated DNA demethylation, were profoundly increased and required for active DNA demethylation of the Prdm16 promoter. AMPKα1 ablation reduced isocitrate dehydrogenase 2 activity and cellular αKG levels. Remarkably, postnatal AMPK activation with AICAR or metformin rescued obesity-induced suppression of brown adipogenesis and thermogenesis. In summary, AMPK is essential for the epigenetic control of BAT development through αKG, thus linking a metabolite to progenitor cell differentiation and thermogenesis.
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AKG treatment increases BAT thermogenesis and decreases fat mass.
“On the other hand, we found AKG treatment increases BAT thermogenesis and decreases fat mass, which is consistent with the previous report that AKG increases BAT adipogenesis and thermogenesis via an epigenetic way (Yang et al, 2016).”
From Exercise‐induced α‐ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1‐dependent adrenal activation (2020) · cites this paper as Yang et al, 2016
The Results section reports that αKG supplementation enhanced brown adipogenesis in cultured cells and increased a marker of DNA demethylation in the Prdm16 promoter. The paper links this pathway to BAT thermogenesis, but its reported rescue of thermogenesis used the AMPK activators AICAR and metformin, not direct αKG treatment. The citing authors’ finding about decreased fat mass is their own, rather than a finding attributed to this source. (LLM, conf=0.86)
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- Harms MJ Ishibashi J Wang W Lim HW Goyama S Sato T Kurokawa M Won KJ Seale P Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice Cell metabolism 2014b 19 593 604 24703692 PMC4012340
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“On the other hand, we found AKG treatment increases BAT thermogenesis and decreases fat mass, which is consistent with the previous report that AKG increases BAT adipogenesis and thermogenesis via an epigenetic way (Yang et al , 2016).”
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- Authors
- Yang, Q., Liang, X., Sun, X., Zhang, L., Fu, X., Rogers, C. J., Berim, A., Zhang, S., Wang, S., Wang, B., Foretz, M., Viollet, B., Gang, D. R., Rodgers, B. D., Zhu, M.-J., & Du, M.
- Affiliations
- Washington State University (US)
- Chinese Academy of Agricultural Sciences (CN)
- Centre National de la Recherche Scientifique (FR)
- Beijing Advanced Innovation Center for Food Nutrition and Human Health (CN)
- Corresponding author
- Du, Min
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 24
- Issue
- 4
- Pages
- 542-554
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5061633
- OpenAlex
- W2519117803
- Cited by
- 237
- References
- 57
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 16 · 2023: 27 · 2022: 40 · 2021: 30 · 2020: 30 · 2019: 23 · 2018: 20 · 2017: 19 · 2016: 5
- FWCI
- 17.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Civil War Book Review (submittedVersion)
- Funders
- National Institute on Aging (R21AG049976)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD067449)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- AMPK, alpha-ketoglutarate, DNA demethylation, PRDM16, brown adipogenesis, brown adipose tissue, thermogenesis, IDH2, epigenetic regulation, obesity, metformin, AICAR, AMPKα1
- MeSH terms
- Animals, Adipose Tissue, Brown, Cell Line, DNA-Binding Proteins, Ketoglutaric Acids, Mice, Obese, Obesity, Promoter Regions, Genetic, Transcription Factors, Weaning, Stromal Cells, Gene Deletion, Mice, Knockout, DNA Methylation, Adipogenesis, AMP-Activated Protein Kinases
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