Obesity caused by an OVOL2 mutation reveals dual roles of OVOL2 in promoting thermogenesis and limiting white adipogenesis

Zhao Zhang, Yiao Jiang, Lijing Su, Sara Ludwig, Xuechun Zhang, Miao Tang, Xiaohong Li, Priscilla Anderton, Xiaoming Zhan, Mihwa Choi, Jamie L Russell, Chun Hui Bu, Stephen Lyon, Darui Xu, Sara Hildebrand, Lindsay Scott, Jiexia Quan, Rochelle Simpson, Qihua Sun, Baifang QinTiffany Collie, Meron Tadesse, Eva Marie Y. Moresco, Bruce Beutler

Research output: Contribution to journalArticlepeer-review

Abstract

Using random germline mutagenesis in mice, we identified a viable hypomorphic allele (boh) of the transcription-factor-encoding gene Ovol2 that resulted in obesity, which initially developed with normal food intake and physical activity but decreased energy expenditure. Fat weight was dramatically increased, while lean weight was reduced in 12-week-old boh homozygous mice, culminating by 24 weeks in massive obesity, hepatosteatosis, insulin resistance, and diabetes. The Ovol2boh/boh genotype augmented obesity in Lepob/ob mice, and pair-feeding failed to normalize obesity in Ovol2boh/boh mice. OVOL2-deficient mice were extremely cold intolerant. OVOL2 is essential for brown/beige adipose tissue-mediated thermogenesis. In white adipose tissues, OVOL2 limited adipogenesis by blocking C/EBPα engagement of its transcriptional targets. Overexpression of OVOL2 in adipocytes of mice fed with a high-fat diet reduced total body and liver fat and improved insulin sensitivity. Our data reveal that OVOL2 plays dual functions in thermogenesis and adipogenesis to maintain energy balance.

Original languageEnglish (US)
Pages (from-to)1860-1874.e4
JournalCell Metabolism
Volume34
Issue number11
DOIs
StatePublished - Nov 1 2022

Keywords

  • adipogenesis
  • brown adipose tissue
  • C/EBPα
  • cold intolerance
  • obesity
  • OVOL2
  • thermogenesis
  • UCP1

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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