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