1. Academic Validation
  2. Screening of FDA-approved drugs identifies sutent as a modulator of UCP1 expression in brown adipose tissue

Screening of FDA-approved drugs identifies sutent as a modulator of UCP1 expression in brown adipose tissue

  • EBioMedicine. 2018 Nov;37:344-355. doi: 10.1016/j.ebiom.2018.10.019.
Yan Qiu 1 Yingmin Sun 1 Danqing Xu 2 Yuanyuan Yang 1 Xiaojian Liu 1 Yuda Wei 1 Yanhao Chen 1 Zhuanghui Feng 1 Shuang Li 1 Md Reyad-Ul Ferdous 1 Yongxu Zhao 1 Hongxi Xu 3 Yuanzhi Lao 4 Qiurong Ding 5
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, PR China.
  • 2 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.
  • 3 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, PR China.
  • 4 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, PR China. Electronic address: [email protected].
  • 5 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, PR China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, PR China. Electronic address: [email protected].
Abstract

Background: The pharmacological activation of thermogenesis in brown adipose tissue has long been considered promising strategies to treat obesity. However, identification of safe and effective agents remains a challenge. In this study, we addressed this challenge by developing a cellular system with a fluorescence readout, and applied in a high-throughput manner to screen for FDA-approved drugs that may activate endogenous UCP1 expression in adipocytes.

Methods: We have generated a Ucp1-2A-GFP reporter mouse, in which GFP intensity serves as a surrogate of the endogenous expression level of UCP1 protein; and immortalized brown adipocytes were derived from this mouse model and applied in drug screening. Candidate drugs were further tested in mouse models either fed with normal chow or high fat diet to induce obesity.

Findings: By using the cellular screening platform, we identified a group of FDA-approved drugs that can upregulate UCP1 expression in brown adipocyte, including previously known UCP1 activators and new candidate drugs. Further studies focusing on a previously unreported drug-sutent, revealed that sutent treatment could increase the energy expenditure and inhibit lipid synthesis in mouse adipose and liver tissues, resulting in improved metabolism and resistance to obesity.

Interpretation: This study offered an easy-to-use cellular screening system for UCP1 activators, and provided a candidate list of FDA-approved drugs that can potentially treat obesity. Further study of these candidates may shed new LIGHT on the drug discovery towards obesity. FUND: National Key Research and Development Program and the Strategic Priority Research Program of the Chinese Academy of Sciences, etc. (250 words).

Keywords

Brown adipose; FDA-approved drug library; Obesity; Sutent; Uncoupling protein 1.

Figures
Products