@article{523e4210bda947c382830cf3da9f30ac,
title = "Obesity caused by an OVOL2 mutation reveals dual roles of OVOL2 in promoting thermogenesis and limiting white adipogenesis",
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.",
keywords = "C/EBPα, OVOL2, UCP1, adipogenesis, brown adipose tissue, cold intolerance, obesity, thermogenesis",
author = "Zhao Zhang and Yiao Jiang and Lijing Su and Sara Ludwig and Xuechun Zhang and Miao Tang and Xiaohong Li and Priscilla Anderton and Xiaoming Zhan and Mihwa Choi and Jamie Russell and Bu, {Chun Hui} and Stephen Lyon and Darui Xu and Sara Hildebrand and Lindsay Scott and Jiexia Quan and Rochelle Simpson and Qihua Sun and Baifang Qin and Tiffany Collie and Meron Tadesse and Moresco, {Eva Marie Y.} and Bruce Beutler",
note = "Funding Information: We thank the metabolic phenotyping, histopathology, mass spectrometry, and transgenic cores of the University of Texas Southwestern Medical Center for providing excellent services. We thank Dr. Philipp Scherer and Dr. Yu An at the University of Texas Southwestern Medical Center for providing Apn-rtTA mice and helping with Seahorse analysis. This work was supported by the National Institutes of Health (K99 DK115766 and R00 DK115766, Z.Z.; R01 AI125581 and U19 AI100627, B.B.) and the Lyda Hill foundation (B.B.). Conceptualization, Z.Z. and B.B.; data curation, Z.Z. and B.B.; formal analysis, Z.Z. and B.B.; funding acquisition, Z.Z. and B.B.; investigation, Z.Z. Y.J. L.S. and X. Zhang; methodology, Z.Z. and B.B.; project administration, Z.Z. and B.B.; resources, Z.Z. S.L. M.T. X.L. P.A. X. Zhan, M.C. J.R. L.S. J.Q. R.S. Q.S. B.Q. T.C. M.T. and B.B.; software, C.-H.B. S.L. D.X. S.H. and B.B.; supervision, Z.Z. and B.B.; validation, Z.Z.; visualization, Z.Z.; writing – original draft, Z.Z.; writing – review & editing, Z.Z. E.M.Y.M. and B.B. Z.Z. L.S. and B.B. are inventors on a patent related to these findings. Funding Information: We thank the metabolic phenotyping, histopathology, mass spectrometry, and transgenic cores of the University of Texas Southwestern Medical Center for providing excellent services. We thank Dr. Philipp Scherer and Dr. Yu An at the University of Texas Southwestern Medical Center for providing Apn-rtTA mice and helping with Seahorse analysis. This work was supported by the National Institutes of Health (K99 DK115766 and R00 DK115766, Z.Z.; R01 AI125581 and U19 AI100627, B.B.) and the Lyda Hill foundation (B.B.). Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = nov,
day = "1",
doi = "10.1016/j.cmet.2022.09.018",
language = "English (US)",
volume = "34",
pages = "1860--1874.e4",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "11",
}