Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis.
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 Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mφs (macrophages) from Atg7 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 Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mφs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 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.
['Lee|Hae-Youn|HY|', 'Kim|Jinyoung|J|', 'Quan|Wenying|W|', 'Lee|June-Chul|JC|', 'Kim|Min-Soo|MS|', 'Kim|Seok-Hyung|SH|', 'Bae|Jin-Woo|JW|', 'Hur|Kyu Yeon|KY|', 'Lee|Myung-Shik|MS|']
D000818:Animals D001343:Autophagy D000071193:Autophagy-Related Protein 7 D001835:Body Weight D003092:Colitis D016207:Cytokines D003920:Diabetes Mellitus D003924:Diabetes Mellitus, Type 2 D004195:Disease Models, Animal D018450:Disease Progression D004721:Endoplasmic Reticulum D005260:Female D058847:Inflammasomes D007249:Inflammation D053583:Interleukin-1beta D008055:Lipids D008264:Macrophages D008297:Male D024821:Metabolic Syndrome D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008928:Mitochondria D009765:Obesity D017382:Reactive Oxygen Species D017154:Stromal Cells D050378:T-Lymphocytes, Regulatory
autophagy diabetes colitis inflammasome macrophages obesity