Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling

Adipose tissue remodels via hypertrophy or hyperplasia in response to nutrient status, but the mechanisms governing these expansion modes remain unclear. Here, we identify a nutrient-sensitive epigenetic circuit linking glucose metabolism to chromatin remodeling during adipogenesis. Upon glucose stimulation, α-ketoglutarate (α-KG) accumulates in the nucleus and activates the histone demethylase JMJD1A to remove repressive histone H3 lysine 9 dimethylation (H3K9me2) marks at glycolytic and adipogenic gene loci, including Pparg. JMJD1A is recruited to pre-marked promoter chromatin via nuclear factor IC (NFIC), enabling carbohydrate-responsive element-binding protein (ChREBP) binding and transcriptional activation. This feedforward mechanism couples nutrient flux to chromatin accessibility and gene expression. In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion in visceral fat under nutrient excess. JMJD1A deficiency impairs hyperplasia, exacerbates adipocyte hypertrophy, and induces local inflammation. These findings define a glucose-α-KG-JMJD1A-ChREBP axis regulating depot-specific adipogenesis and uncover a chromatin-based mechanism by which glucose metabolism governs adaptive adipose tissue remodeling.

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Journal
Cell Reports
Published
2025-07-26
DOI
https://doi.org/10.1016/j.celrep.2025.116060
Primary Topic
Epigenetics and DNA Methylation
Type
article
Field-Weighted Citation Impact
0.00

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article

Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling

Hiroyuki Aburatani, Makoto Arai, Yoshihiro Matsumura, Juro Sakai et al.
Cell Reports
Epigenetics and DNA Methylation
article

Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling

Hiroyuki Aburatani, Makoto Arai, Yoshihiro Matsumura, Juro Sakai, Tsuyoshi Osawa, Toshiya Tanaka, Ryo Ito, Hiroshi Kimurâ, Tetsuro Komatsu, Hina Sagae, Makoto Tachibana, Chaoran Yang, Munetaka Nitta, Chenxu Yang, Takeshi Yoneshiro, Tomoyoshi Soga, Eko Fuji Ariyanto, Youichiro Wada, Takeshi Inagaki, Tomohiro Suzuki, Hyunmi Choi, Yoichi Shinkai, Fumie Kawashima, Hitomi Jin, Timothy F. Osborne, Hiroki Takahashi, Ji Zhang, Shiyu Xie, Eri Kobayashi, Bohao Liu, Yuchen Wei, Tatsuhiko Kodama, Tomofumi Ishitsuka, Debby Mirani Lubis
article en

Abstract

Adipose tissue remodels via hypertrophy or hyperplasia in response to nutrient status, but the mechanisms governing these expansion modes remain unclear. Here, we identify a nutrient-sensitive epigenetic circuit linking glucose metabolism to chromatin remodeling during adipogenesis. Upon glucose stimulation, α-ketoglutarate (α-KG) accumulates in the nucleus and activates the histone demethylase JMJD1A to remove repressive histone H3 lysine 9 dimethylation (H3K9me2) marks at glycolytic and adipogenic gene loci, including Pparg. JMJD1A is recruited to pre-marked promoter chromatin via nuclear factor IC (NFIC), enabling carbohydrate-responsive element-binding protein (ChREBP) binding and transcriptional activation. This feedforward mechanism couples nutrient flux to chromatin accessibility and gene expression. In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion in visceral fat under nutrient excess. JMJD1A deficiency impairs hyperplasia, exacerbates adipocyte hypertrophy, and induces local inflammation. These findings define a glucose-α-KG-JMJD1A-ChREBP axis regulating depot-specific adipogenesis and uncover a chromatin-based mechanism by which glucose metabolism governs adaptive adipose tissue remodeling.

Cell ReportsVol. 44(8)
Tokyo Institute of Technology (JP), Johns Hopkins University (US), Tokyo University of Technology (JP), Tokyo University of Science (JP), Gunma University (JP), Tohoku University (JP), Akita University (JP), Keio University (JP), Japan Agency for Medical Research and Development (JP), Johns Hopkins All Children's Hospital (US), Pioneer (Japan) (JP), The University of Tokyo (JP), Padjadjaran University (ID), The University of Osaka (JP)
Novartis Foundation, Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Secom Science and Technology Foundation, University of Tokyo, Japan Society for the Promotion of Science, Core Research for Evolutional Science and Technology
Zero hunger
Openalex Percentile: Top 84%
Epigenetics and DNA Methylation
DOIOpen Access PDFOpenAlex
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