[논문]GATA3 induces the upregulation of UCP-1 by directly binding to PGC-1α during adipose tissue browning

Son, Min Jeong; Oh, Kyoung-Jin; Park, Anna; Kwon, Min-Gi; Suh, Jae Myoung; Kim, Il-Chul; Kim, Seyun; Lee, Sang Chul; Kim, Won Kon; Bae, Kwang-Hee

doi:10.1016/j.metabol.2020.154280

[해외논문] GATA3 induces the upregulation of UCP-1 by directly binding to PGC-1α during adipose tissue browning

Metabolism : clinical and experimental, v.109, 2020년, pp.154280 -

Son, Min Jeong (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) , Oh, Kyoung-Jin (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Park, Anna (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) , Kwon, Min-Gi (Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) , Suh, Jae Myoung (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST)) , Kim, Il-Chul (Department of Biology, Chonnam National University) , Kim, Seyun (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) , Lee, Sang Chul (Metabolic Regulation Research Center, Korea Research Institute of Bioscience) , Kim, Won Kon , Bae, Kwang-Hee

Abstract ▼ AI-Helper

Abstract Objective Obesity is recognized as the cause of multiple metabolic diseases and is rapidly increasing worldwide. As obesity is due to an imbalance in energy homeostasis, the promotion of energy consumption through browning of white adipose tissue (WAT) has emerged as a promising therapeutic strategy to counter the obesity epidemic. However, the molecular mechanisms of the browning process are not well understood. In this study, we investigated the effects of the GATA family of transcription factors on the browning process. Methods We used qPCR to analyze the expression of GATA family members during WAT browning. In order to investigate the function of GATA3 in the browning process, we used the lentivirus system for the ectopic expression and knockdown of GATA3. Western blot and real-time qPCR analyses revealed the regulation of thermogenic genes upon ectopic expression and knockdown of GATA3. Luciferase reporter assays, co-immunoprecipitation, and chromatin immunoprecipitation were performed to demonstrate that GATA3 interacts with proliferator-activated receptor-γ co-activator-1α (PGC-1α) to regulate the promoter activity of uncoupling protein-1 (UCP-1). Enhanced energy expenditure by GATA3 was confirmed using oxygen consumption assays, and the mitochondrial content was assessed using MitoTracker. Furthermore, we examined the in vivo effects of lentiviral GATA3 overexpression and knockdown in inguinal adipose tissue of mice. Results Gata3 expression levels were significantly elevated in the inguinal adipose tissue of mice exposed to cold conditions. Ectopic expression of GATA3 enhanced the expression of UCP-1 and thermogenic genes upon treatment with norepinephrine whereas GATA3 knockdown had the opposite effect. Luciferase reporter assays using the UCP-1 promoter region showed that UCP-1 expression was increased in a dose-dependent manner by GATA3 regardless of norepinephrine treatment. GATA3 was found to directly bind to the promoter region of UCP-1. Furthermore, our results indicated that GATA3 interacts with the transcriptional coactivator PGC-1α to increase the expression of UCP-1. Taken together, we demonstrate that GATA3 has an important role in enhancing energy expenditure by increasing the expression of thermogenic genes both in vitro and in vivo. Conclusion GATA3 may represent a promising target for the prevention and treatment of obesity by regulating thermogenic capacity. Highlights GATA3 expression was induced upon cold exposure in mice. Ectopic expression of GATA3 induced thermogenic program, whereas GATA3 knockdown decreased thermogenic activation. GATA3 induced increased UCP-1 expression by binding to its promoter region with PGC-1α. GATA3 induced the in vivo activation of the thermogenic program. GATA3 may represent a promising target for the prevention and treatment of obesity by regulating thermogenic capacity.

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