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

作者：Lee Hae Youn; Kim Jinyoung; Quan Wenying; Lee June Chul; Kim Min Soo; Kim Seok Hyung; Bae Jin Woo; Hur Kyu Yeon; Lee Myung Shik^*

来源：Autophagy, 2016, 12(8): 1390-1403.

DOI：10.1080/15548627.2016.1184799

• autophagy
• colitis
• diabetes
• inflammasome
• macrophages
• obesity

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. M phi s (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 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 M phi s from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient M phi s 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 M phi s is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in M phi s may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.

• 出版日期2016