2. Academic Validation
  3. Kdm2a inhibition in skeletal muscle improves metabolic flexibility in obesity

Kdm2a inhibition in skeletal muscle improves metabolic flexibility in obesity

  • Nat Metab. 2025 Jan 27. doi: 10.1038/s42255-024-01210-9.
Yuhan Wang # 1,  Hao Xie # 1 2,  Qianrui Liu # 1,  Na Wang # 1,  Xi Luo 1,  Fei Sun 1,  Jinghan Zhu 3,  Ruihan Dong 1,  Yi Wang 1,  Jia Gao 1,  Zhichao Gao 1,  Teng Huang 1,  Xin Liu 4,  Qilin Yu 1,  Ting Wang 1,  Yang Li 1,  Danni Song 1,  Shiwei Liu 5,  Shu Zhang 6,  Hao Yin 7,  Wen Kong 8,  Cong-Yi Wang 9 10
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, The Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, China.
  • 3 Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Department of Interventional Radiology, Renmin Hospital of Wuhan University, Wuhan, China.
  • 5 Tongji Shanxi Hospital, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, China.
  • 6 Department of Respiratory and Critical Care Medicine, The Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. szhang@tjh.tjmu.edu.cn.
  • 7 Organ Transplant Center, Shanghai Changzheng Hospital (Second Affiliated Hospital of Naval Medical University), Shanghai, China. yinhaoshanghai@163.com.
  • 8 Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wenly-kong@163.com.
  • 9 Tongji Shanxi Hospital, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, China. wangcy@tjh.tjmu.edu.cn.
  • 10 The Center for Biomedical Research, Tongji Hospital Research Building, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wangcy@tjh.tjmu.edu.cn.
  • # Contributed equally.
PMID: 39870955 DOI: 10.1038/s42255-024-01210-9
Abstract

Skeletal muscle is a critical organ in maintaining homoeostasis against metabolic stress, and histone post-translational modifications are pivotal in those processes. However, the intricate nature of histone methylation in skeletal muscle and its impact on metabolic homoeostasis have yet to be elucidated. Here, we report that mitochondria-rich slow-twitch myofibers are characterized by significantly higher levels of H3K36me2 along with repressed expression of Kdm2a, an Enzyme that specifically catalyses H3K36me2 demethylation. Deletion or inhibition of Kdm2a shifts fuel use from glucose under cold challenge to lipids under obese conditions by increasing the proportion of mitochondria-rich slow-twitch myofibers. This protects mice against cold insults and high-fat-diet-induced obesity and Insulin resistance. Mechanistically, Kdm2a deficiency leads to a marked increase in H3K36me2 levels, which then promotes the recruitment of Mrg15 to the Esrrg locus to process its precursor messenger RNA splicing, thereby reshaping skeletal muscle metabolic profiles to induce slow-twitch myofiber transition. Collectively, our data support the role of Kdm2a as a viable target against metabolic stress.

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