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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 (KO) of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from developing 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 KO mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-α-stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. With results 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.

Original languageEnglish (US)
Pages (from-to)1303-1316
Number of pages14
JournalDiabetes
Volume70
Issue number6
DOIs
StatePublished - Jun 1 2021

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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