American Diabetes Association
2 files

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

posted on 2021-03-18, 20:45 authored 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) .