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Obesity Induces Preadipocyte CD36 Expression Promoting Inflammation via the Disruption of Lysosomal Calcium Homeostasis and Lysosome Function
34 Pages Posted: 11 Mar 2020
More...Abstract
Background: Preadipocyte is one of the major contributors to obesity-induced inflammation. The impairment of autophagic flux by defective lysosomal function has been observed in adipose tissue from obese mice. While the fatty acid translocase CD36 is an important immuno-metabolic receptor, it remains unclear whether preadipocyte CD36 is involved in adipose tissue inflammation and whether CD36 regulates lysosomal function.
Methods: Using visceral adipose tissue from obese patients, a high-fat diet (HFD)-induced obese mice model, primary mouse preadipocytes and 3T3L1 cells we analyzed whether and how preadipocyte CD36 modulates lysosomal function and adipose tissue inflammation. Findings: CD36 expression in preadipocytes is induced in obese patients and HFD-fed mice, accompanied with decreased lysosomal numbers and impaired lysosomal acidification. CD36 knockout protects lysosomal impairment in primary preadipocytes from mice. In vitro, CD36 interacts with Fyn to phosphorylate and activate Inositol (1,4,5)-trisphosphate receptor 1 (IP3R1), causing excess calcium transport from endoplasmic reticulum (ER) to lysosome, which results in lysosomal impairment and inflammation. Moreover, IP3R inhibitor 2-aminoethoxydiphenyl borate (2APB) attenuated lysosomal impairment, inflammation and lipid accumulation in CD36-overexpressing preadipocytes.
Interpretation: Our data support that increased CD36 expression in preadipocytes is essential for the development of adipose tissue inflammation. CD36/Fyn/IP3R1-mediated lysosomal calcium overload leads to lysosomal impairment and inflammation in preadipocyte. Thus targeting improving lysosomal calcium homeostasis may represent a novel strategy for treating obesity-induced inflammation.
Funding Statement: This work was supported by National Key R&D Program of China (2018YFC1312700), the National Natural Science Foundation of China (81873569, 81970510, 31971084) and the Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No.KJZD-K201800401, KJQN201900438).
Declaration of Interests: The authors declare that they have no conflict of interest.
Ethics Approval Statement: The study was approved by the Ethics Committees of CQMU, and all subjects provided written informed consent.
All mouse care and experimental procedures were approved by the Institutional Animal Care and Use Committee of CQMU.
Keywords: CD36, preadipocytes, inflammation, lysosomal calcium, IP3R1
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