@article{46808973322d48e8bcbfa0618c4cdcfc,
title = "A unique role of carboxylesterase 3 (CES3) in b-adrenergic signaling–stimulated thermogenesis",
abstract = "Carboxylesterase 3 (Ces3) is a hydrolase with a wide range of activities in liver and adipose tissue. In this study, we identified Ces3 as a major lipid droplet surface-targeting protein in adipose tissue upon cold exposure by liquid chromatography—tandem mass spectrometry. To investigate the function of Ces3 in the b-adrenergic signaling–activated adipocytes, we applied WWL229, a specific Ces3 inhibitor, or genetic inhibition by siRNA to Ces3 on isoproterenol (ISO)–treated 3T3-L1 and brown adipocyte cells. We found that blockage of Ces3 by WWL229 or siRNA dramatically attenuated the ISO-induced lipolytic effect in the cells. Furthermore, Ces3 inhibition led to impaired mitochondrial function measured by Seahorse. Interestingly, Ces3 inhibition attenuated an ISO-induced thermogenic program in adipocytes by downregulating Ucp1 and Pgc1a genes via peroxisome proliferator–activated receptor g. We further confirmed the effects of Ces3 inhibition in vivo by showing that the thermogenesis in adipose tissues was significantly attenuated in WWL229-treated or adipose tissue–specific Ces3 heterozygous knockout (Adn-Cre-Ces3flx/wt) mice. As a result, the mice exhibited dramatically impaired ability to defend their body temperature in coldness. In conclusion, our study highlights a lipolytic signaling induced by Ces3 as a unique process to regulate thermogenesis in adipose tissue.",
author = "Li Yang and Xin Li and Hui Tang and Zhanguo Gao and Kangling Zhang and Kai Sun",
note = "Funding Information: This study was supported by National Institutes of Health grant R01-DK-109001 (to K.S.) and supported in part by the Clinical and Translational Proteomics Service Center at the University of Texas Health Science Center at Houston. Funding Information: Acknowledgments. The authors thank Dr. Baharan Fekry and Alexes C. Daquinag at the University of Texas Health Science Center at Houston (Houston, TX) for the technical support, Dr. Zhengmei Mao in the microscopy core of the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (Houston, TX) for assistance on imaging and tissue processing, as well as Dr. Li Li and Dr. Sheng Pan at the Clinical and Translational Proteomics Service Center at the University of Texas Health Science Center at Houston for the LC-MS/ MS analysis. The authors also thank Dr. Yanqiao Zhang at Northeast Ohio Medical University (Rootstown, OH) for the gift of the 3⨯ PPRE-luc (for PPARa) plasmid, Dr. Jiandie Lin at the University of Michigan (Ann Arbor, MI) for the BAC cell line, and Dr. Richard Lehner from the University of Alberta (Edmonton, Alberta, Canada) for the Ces3flx/flx mouse model. Funding. This study was supported by National Institutes of Health grant R01-DK-109001 (to K.S.) and supported in part by the Clinical and Translational Proteomics Service Center at the University of Texas Health Science Center at Houston. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. L.Y. and X.L. performed the experiments, analyzed the data, and assisted with manuscript writing. H.T. and K.Z. contributed to the LC-MS/MS analyses. Z.G. contributed to the research on BAC adipocytes and Seahorse assays. K.S. conceived and designed the research, provided supervision, and wrote the manuscript. K.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association.",
year = "2019",
month = jun,
day = "1",
doi = "10.2337/db18-1210",
language = "English (US)",
volume = "68",
pages = "1178--1196",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "6",
}