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

IF 6.9 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-07-26 DOI:10.1016/j.celrep.2025.116060

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

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引用次数: 0

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.

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葡萄糖激活的JMJD1A通过α-酮戊二酸依赖的染色质重塑驱动内脏脂肪形成。

脂肪组织在营养状态下通过肥大或增生进行重塑，但控制这些扩张模式的机制尚不清楚。在这里，我们确定了一个营养敏感的表观遗传回路，将脂肪形成过程中的葡萄糖代谢与染色质重塑联系起来。葡萄糖刺激后，α-酮戊二酸（α-KG）在细胞核内积累，激活组蛋白去甲基化酶JMJD1A，去除糖酵解和脂肪生成基因位点（包括Pparg）上的抑制组蛋白H3赖氨酸9二甲基化（H3K9me2）标记。JMJD1A通过核因子IC （NFIC）被募集到预先标记的启动子染色质上，使碳水化合物反应元件结合蛋白（ChREBP）结合和转录激活。这种前馈机制将营养通量与染色质可及性和基因表达结合起来。在体内，JMJD1A在营养过剩的情况下对内脏脂肪的新生脂肪形成和增生性扩张至关重要。JMJD1A缺乏损害增生，加剧脂肪细胞肥大，并诱发局部炎症。这些发现定义了葡萄糖-α-KG-JMJD1A-ChREBP轴调节储存库特异性脂肪形成，并揭示了葡萄糖代谢控制适应性脂肪组织重塑的基于染色质的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.