2. Academic Validation
  3. Selective PPARγ modulator Diosmin improves insulin sensitivity and promotes browning of white fat

Selective PPARγ modulator Diosmin improves insulin sensitivity and promotes browning of white fat

  • J Biol Chem. 2023 Feb 23;103059. doi: 10.1016/j.jbc.2023.103059.
Jian Yu 1,  Yepeng Hu 2,  Maozheng Sheng 3,  Mingyuan Gao 3,  Wenxiu Guo 3,  Zhe Zhang 3,  Dongmei Wang 3,  Xia Wu 3,  Jin Li 4,  Yantao Chen 5,  Wenjun Zhao 3,  Caizhi Liu 3,  Xiangdi Cui 3,  Xin Chen 3,  Cheng Zhao 3,  Huang Chen 3,  Junjie Xiao 4,  Shijie Chen 5,  Cheng Luo 5,  Lingyan Xu 6,  Xuejiang Gu 7,  Xinran Ma 8
Affiliations

Affiliations

  • 1 Department of Endocrine and Metabolic Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China; Joint Center for Translational Medicine, Fengxian District Central Hospital, Fengxian District, Shanghai, 200241, China.
  • 2 Department of Endocrine and Metabolic Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 4 Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Sciences, Shanghai University, Shanghai, 200444, China.
  • 5 Drug Discovery and Design Center, The Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 6 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: [email protected].
  • 7 Department of Endocrine and Metabolic Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. Electronic address: [email protected].
  • 8 Department of Endocrine and Metabolic Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China; Joint Center for Translational Medicine, Fengxian District Central Hospital, Fengxian District, Shanghai, 200241, China; Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing 401120, China. Electronic address: [email protected].
PMID: 36841479 DOI: 10.1016/j.jbc.2023.103059
Abstract

Peroxisome Proliferator-activated Receptor γ (PPARγ) is a master regulator of adipocyte differentiation, glucolipid metabolism, and inflammation. Thiazolidinediones (TZDs) are PPARγ full agonists with potent insulin-sensitizing effects while their oral usage is restricted due to unwanted side effects, including obesity and cardiovascular risks. Here, via virtual screening, microscale thermophoresis analysis, and molecular confirmation, we demonstrate that Diosmin, a natural compound of wide and long-term clinical use, is a selective PPARγ Modulator that binds to PPARγ and blocks PPARγ phosphorylation with weak transcriptional activity. Local Diosmin administration in subcutaneous fat (iWAT) improved Insulin sensitivity and attenuated obesity via enhancing browning of white fat and energy expenditure. Besides, Diosmin ameliorated inflammation in WAT and liver and reduced hepatic steatosis. Of note, we determined that iWAT local administration of Diosmin did not exhibit obvious side effects. Taken together, the present study demonstrated that iWAT local delivery of Diosmin protected mice from diet-induced Insulin resistance, obesity and fatty liver by blocking PPARγ phosphorylation, without apparent side effects, making it a potential therapeutic agent for the treatment of metabolic diseases.

Keywords

Browning of white fat tissue; Diosmin; Insulin sensitivity; PPARγ phosphorylation; Selective PPARγ modulator.

Figures
Products