Abstract
Adipose tissue inflammation participates in the pathogenesis of type 2 diabetes in obesity. While the activation of the multiprotein complex known as NLRP3 inflammasome and subsequent release of IL-1β contribute to the development of adipose tissue inflammation and insulin resistance, the mechanisms of its regulation remain unclear. Here we revealed that APPL1, an adaptor protein essential for adiponectin and insulin signaling, is upregulated in the stromal vascular fraction of visceral fat of db/db diabetic mice. Also, lack of APPL1 in bone marrow-derived macrophages specifically enhanced inflammatory response mediated by NLRP3 inflammasome. Mice with hematopoietic cells-specific APPL1 deficiency (APPL1-BMT-KO) were then generated using bone marrow transplantation approach and subjected to high-fat diet (HFD) feeding. After 36 weeks of HFD feeding, APPL1-BMT-KO mice exhibited increased insulin resistance and glucose intolerance, accompanied with elevated IL-1β in serum, liver and epididymal adipose tissue and impaired Akt phosphorylation in the subcutaneous adipose tissue and liver. In vitro experiments suggest that ablation of APPL1 in bone marrow-derived macrophages promotes IL-1β secretion by enhancing ROS generation, which is an important intracellular signal for NLRP3 inflammasome activation. Pharmacological inhibition of intracellular and mitochondrial ROS successfully abrogated the upregulation of IL-1β secretion in APPL1 deficient macrophages. In this study, we demonstrated the novel role of APPL1 in alleviating macrophage-mediated adipose tissue inflammation and insulin resistance. Lack of APPL1 in macrophages promotes ROS generation and NLRP3 inflammasome activation, which causes enhanced IL-1β secretion in adipose tissue and the development of insulin resistance. Disclosure K.K.L. Wu: None. A. Xu: None. K.K. Cheng: None. Funding Research Grants Council of Hong Kong (171018/15M)
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