Rna M6 a Methylation Regulates Glycolysis of Beige Fat and Contributes to Systemic Metabolic Homeostasis

Yu Li; Yankang Zhang; Ting Zhang; Xiaodan Ping; Dongmei Wang; Yanru Chen; Jian Yu; Caizhi Liu; Ziqi Liu; Yuhan Zheng; Yongfeng Yang; Chengchao Ruan; Dali Li; Zhenyu Du; Jiqiu Wang; Lingyan Xu; Xinran Ma

doi:10.1002/advs.202300436

Rna M⁶ a Methylation Regulates Glycolysis of Beige Fat and Contributes to Systemic Metabolic Homeostasis

Adv Sci (Weinh). 2023 Sep;10(25):e2300436. doi: 10.1002/advs.202300436. Epub 2023 Jul 5.

Authors

Yu Li^{1

2}, Yankang Zhang¹, Ting Zhang¹, Xiaodan Ping¹, Dongmei Wang¹, Yanru Chen³, Jian Yu^{1

4}, Caizhi Liu¹, Ziqi Liu¹, Yuhan Zheng¹, Yongfeng Yang⁵, Chengchao Ruan⁵, Dali Li^{1

6}, Zhenyu Du¹, Jiqiu Wang³, Lingyan Xu¹, Xinran Ma^{1

2

4

6}

Affiliations

¹ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
² Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, 401120, China.
³ Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁴ Department of Endocrinology and Metabolism, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, 201499, China.
⁵ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
⁶ Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai, 200241, China.

Abstract

N6-methyladenosine (m⁶ A) modification has been implicated in the progression of obesity and metabolic diseases. However, its impact on beige fat biology is not well understood. Here, via m⁶ A-sequencing and RNA-sequencing, this work reports that upon beige adipocytes activation, glycolytic genes undergo major events of m⁶ A modification and transcriptional activation. Genetic ablation of m⁶ A writer Mettl3 in fat tissues reveals that Mettl3 deficiency in mature beige adipocytes leads to suppressed glycolytic capability and thermogenesis, as well as reduced preadipocytes proliferation via glycolytic product lactate. In addition, specific modulation of Mettl3 in beige fat via AAV delivery demonstrates consistently Mettl3's role in glucose metabolism, thermogenesis, and beige fat hyperplasia. Mechanistically, Mettl3 and m⁶ A reader Igf2bp2 control mRNA stability of key glycolytic genes in beige adipocytes. Overall, these findings highlight the significance of m⁶ A on fat biology and systemic energy homeostasis.

Keywords: Mettl3; N6-methyladenosine; beige fat; energy homeostasis; glycolysis; preadipocytes proliferation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue, Beige* / metabolism
Glycolysis* / genetics
Homeostasis / genetics
Methylation
RNA / metabolism

Substances

RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding