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

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.