Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation

Wenmin Xia, Preethi Veeragandham, Yu Cao, Yayun Xu, Torrey E. Rhyne, Jiaxin Qian, Chao Wei Hung, Peng Zhao, Ying Jones, Hui Gao, Christopher Liddle, Ruth T. Yu, Michael Downes, Ronald M. Evans, Mikael Rydén, Martin Wabitsch, Zichen Wang, Hiroyuki Hakozaki, Johannes Schöneberg, Shannon M. ReillyJianfeng Huang, Alan R. Saltiel

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

Original languageEnglish (US)
Pages (from-to)273-289
Number of pages17
JournalNature Metabolism
Issue number2
StatePublished - Feb 2024

ASJC Scopus subject areas

  • Physiology (medical)
  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology


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