APPL2 Promotes Inflammation in Mouse Liver by Negative Regulation of Adiponectin Signaling

Abstract

Adiponectin is an insulin sensitizer that exerts antidiabetes and anti-inflammation functions. Adiponectin signaling is negatively regulated by the adaptor protein APPL2 in cells, yet the in vivo roles of APPL2 remains largely unknown. In this study, we show that liver-specific knockout of APPL2 improved insulin sensitivity and enhanced adiponectin signaling in high fat diet (HFD)-fed mice. The liver-specific APPL2 knockout mice (APPL2LKO) had less macrophage infiltration in liver tissues compared with their wild type controls and were resistant to LPS-induced expression of inflammatory genes such as IL-6, IL-1α, MCP-1, and TNF-α. Pretreatment of macrophage Raw264.7 cells with conditioned media from primary hepatocytes of APPL2LKO mice attenuated LPS-stimulated expression of inflammatory genes and the migration of the cells. The anti-inflammatory effect of APPL2 knockout was significantly reduced in adiponectin and liver-specific APPL2 double knockout mice (AdiponectinKO/APPL2LKO). Taken together, our results show that APPL2 promotes inflammation in mouse liver and the protein exerts a pro-inflammatory role by antagonizing adiponectin signaling. Disclosure J. Ryu: None.