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Clcn3 deficiency ameliorates high-fat diet-induced obesity and adipose tissue macrophage inflammation in mice.

Authors
  • Ma, Ming-Ming1
  • Jin, Chen-Chen1
  • Huang, Xue-Lian2
  • Sun, Lu1
  • Zhou, Hui3
  • Wen, Xue-Jun4
  • Huang, Xiong-Qing5
  • Du, Jie-Yi1
  • Sun, Hong-Shuo6
  • Ren, Zhu-Xiao1
  • Liu, Jie1
  • Guan, Yong-Yuan1
  • Zhao, Xiao-Miao7
  • Wang, Guan-Lei8
  • 1 Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. , (China)
  • 2 Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. , (China)
  • 3 Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. , (China)
  • 4 Institute for Engineering and Medicine, Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 601 West Main Street, Richmond, VA, 23284-3028, USA.
  • 5 Department of Anesthesiology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China. , (China)
  • 6 Departments of Surgery, Physiology and Pharmacology, Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. , (Canada)
  • 7 Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. [email protected] , (China)
  • 8 Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. [email protected] , (China)
Type
Published Article
Journal
Acta Pharmacologica Sinica
Publisher
Springer Nature
Publication Date
Dec 01, 2019
Volume
40
Issue
12
Pages
1532–1543
Identifiers
DOI: 10.1038/s41401-019-0229-5
PMID: 31165783
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Obesity induces accumulation of adipose tissue macrophages (ATMs) and ATM-driven inflammatory responses that promote the development of glucose and lipid metabolism disorders. ClC-3 chloride channel/antiporter, encoded by the Clcn3, is critical for some basic cellular functions. Our previous work has shown significant alleviation of type 2 diabetes in Clcn3 knockout (Clcn3-/-) mice. In the present study we investigated the role of Clcn3 in high-fat diet (HFD)-induced obesity and ATM inflammation. To establish the mouse obesity model, both Clcn3-/- mice and wild-type mice were fed a HFD for 4 or 16 weeks. The metabolic parameters were assessed and the abdominal total adipose tissue was scanned using computed tomography. Their epididymal fat pad tissue and adipose tissue stromal vascular fraction (SVF) cells were isolated for analyses. We found that the HFD-fed Clcn3-/- mice displayed a significant decrease in obesity-induced body weight gain and abdominal visceral fat accumulation as well as an improvement of glucose and lipid metabolism as compared with HFD-fed wild-type mice. Furthermore, the Clcn3 deficiency significantly attenuated HFD-induced ATM accumulation, HFD-increased F4/80+ CD11c+ CD206- SVF cells as well as HFD-activated TLR-4/NF-κB signaling in epididymal fat tissue. In cultured human THP-1 macrophages, adenovirus-mediated transfer of Clcn3 specific shRNA inhibited, whereas adenovirus-mediated cDNA overexpression of Clcn3 enhanced lipopolysaccharide-induced activation of NF-κB and TLR-4. These results demonstrate a novel role for Clcn3 in HFD-induced obesity and ATM inflammation.

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