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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.

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