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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Nrf2 induces Ucp1 expression in adipocytes in response to β3-AR stimulation and enhances oxygen consumption in high-fat diet-fed obese mice

  • Chang, Seo-Hyuk (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Jang, Jaeyool (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Oh, Seungjun (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Yoon, Jung-Hoon (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Jo, Dong-Gyu (School of Pharmacy, Sungkyunkwan University) ;
  • Yun, Ui Jeong (Department of Food Science and Biotechnology, Sungkyunkwan University) ;
  • Park, Kye Won (Department of Food Science and Biotechnology, Sungkyunkwan University)
  • Received : 2021.02.16
  • Accepted : 2021.03.09
  • Published : 2021.08.31
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Abstract

Cold-induced norepinephrine activates β3-adrenergic receptors (β3-AR) to stimulate the kinase cascade and cAMP-response element-binding protein, leading to the induction of thermogenic gene expression including uncoupling protein 1 (Ucp1). Here, we showed that stimulation of the β3-AR by its agonists isoproterenol and CL316,243 in adipocytes increased the expression of Ucp1 and Heme Oxygenase 1 (Hmox1), the principal Nrf2 target gene, suggesting the functional interaction of Nrf2 with β3-AR signaling. The activation of Nrf2 by tert-butylhydroquinone and reactive oxygen species (ROS) production by glucose oxidase induced both Ucp1 and Hmox1 expression. The increased expression of Ucp1 and Hmox1 was significantly reduced in the presence of a Nrf2 chemical inhibitor or in Nrf2-deleted (knockout) adipocytes. Furthermore, Nrf2 directly activated the Ucp1 promoter, and this required DNA regions located at -3.7 and -2.0 kb of the transcription start site. The CL316,243-induced Ucp1 expression in adipocytes and oxygen consumption in obese mice were partly compromised in the absence of Nrf2 expression. These data provide additional insight into the role of Nrf2 in β3-AR-mediated Ucp1 expression and energy expenditure, further highlighting the utility of Nrf2-mediated thermogenic stimulation as a therapeutic approach to diet-induced obesity.

Keywords

Acknowledgement

This study was supported by grants (NRF-2020R1I1A1A01074938 to U.J.Y., NRF-2020R1A2B5B02001592 to K.W.P.) of the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology, Republic of Korea. This study was also partly supported by The Health Fellowship Foundation to S.H.C.

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