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Adiponectin Alleviates Diet-induced Inflammation in the Liver by Suppressing MCP-1 Expression and Macrophage Infiltration

posted on 18.03.2021, 20:45 by Jiyoon Ryu, Jason T. Hadley, Zhi Li, Feng Dong, Huan Xu, Xiaoban Xin, Ye Zhang, Cang Chen, Senlin Li, Xiaoning Guo, Jared L. Zhao, Robin J. Leach, Muhammad A. Abdul-Ghani, Ralph A. DeFronzo, Amrita Kamat, Feng Liu, Lily Q. Dong
Adiponectin is an adipokine that exerts insulin sensitizing and anti-inflammatory roles in insulin target tissues including liver. While the insulin sensitizing function of adiponectin has been extensively investigated, the precise mechanism by which adiponectin alleviates diet-induced hepatic inflammation remains elusive. Here, we report that hepatocyte-specific knockout of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from high fat diet-induced inflammation, insulin resistance, and glucose intolerance, although it caused fatty liver. The improved anti-inflammatory and insulin sensitizing effects in the APPL2 hepatocyte-specific knockout mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-a-stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. Taken together, our study uncovers a mechanism underlying the anti-inflammatory role of adiponectin in the liver and reveals the hepatic APPL2-mTORC1-MCP-1 axis as a potential target for treating overnutrition-induced inflammation in the liver.


This work was supported in part by American Diabetes Association Basic Science Award (Grant # 7-13-BS-043 to L.Q. D.), NIH R01 grants (DK102965 to L.Q.D and DK114479 to F.L.), DOM clinical and innovative Therapeutic Award pilot program (G1100-22100 to J.R.), and Biomedical Research from the San Antonio Area Foundation (Grant #161926 to J.R), and T32 Biology of Aging Training Grant (T32-AG021890-17 to J.T.H) .