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Autophagy, which is critical for the proper function of organelles such as ER and mitochondria,affects diverse aspects of cellular and whole body metabolism, and its dysregulation has been incriminated in the pathogenesis of metabolic disorders and diabetes.However, the role of autophagy of myeloid cells in the development of adipose tissue inflammation, insulin resistance and type 2 diabetes has not been addressed.We produced mice with myeloid cell-specific deletion of autophagy-related 7 (Atg7), an essential autophagy gene (Atg7DLys mice).While Atg7△Lys mice were metabolically indistinguishable from littermate control mice, they developed diabetes when bred to ob/w mice (Atg7DLys-ob/ob mice), which was accompanied by an increase in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue.Primary macrophages from Atg7DLys mice showed significantly higher interleukin 1b (IL-1b) release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination.Moreover, a decrease in NAD+/NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide was more pronounced in macrophages from Atg7DLys mice, suggesting that mitochondrial dysfunction in autophagy-deficient macrophages leads to an increase in inflammasome activation by lipid injury and metabolic deterioration in Atg7DLys-ob/ob mice.These results suggest that autophagy is important for the control of inflammasome activation in response to lipid or metabolic stress, and autophagy deficiency in macrophages may contribute to the progression of diabetes and metabolic syndrome associated with lipid injury.