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

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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Acknowledgements

This research was supported by the National Natural Science Foundation of China (No 81773722, 81370897, 81471425, and 81370680), the CHINA-CANADA Joint Health Research Program from NSFC-CIHR (No 81361128011), the Guangdong Provincial Department of Science and Technology (No 2016A050502023), the Science and Technology Program of Guangzhou City (No 201607010255 and 201803010092), the Fundamental Research Funds for the Central Universities (No 17ykzd02), and the 111 Project (No B13037) .

Author information

GLW designed the study. XMZ, MMM, CCJ, GLW, XLH, and JYD wrote the manuscript. MMM, CCJ, XLH, LS, HZ, ZXR, and JL performed the experiments. CCJ, XLH, XJW, and XQH analyzed the data; XQH, HSS, and YYG revised the manuscript. GLW and XMZ are the guarantors of this work and, as such, had full access to all the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Correspondence to Xiao-miao Zhao or Guan-lei Wang.

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The authors declare no competing interests.

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Keywords

  • Clcn3
  • obesity
  • adipose tissue
  • inflammation
  • insulin resistance
  • macrophage
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