Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

<p>Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of <i>Atg7</i> (autophagy-related 7), an essential autophagy gene (<i>Atg7</i> conditional knockout [cKO] mice). While <i>Atg7</i> cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to <i>ob/w</i> mice (<i>Atg7</i> cKO-<i>ob/ob</i> mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mφs (macrophages) from <i>Atg7</i> cKO mice showed significantly higher interleukin 1 β release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD⁺:NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mφs from <i>Atg7</i> cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mφs leads to an increase in lipid-induced inflammasome and metabolic deterioration in <i>Atg7</i> cKO-<i>ob/ob</i> mice. <i>Atg7</i> cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mφs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mφs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.