title: Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis.
abstract: 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.
authors.affiliation: a Departments of Medicine , Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Korea.
authors.forename: Hae-Youn
authors.initials: HY
authors.lastname: Lee
authors.affiliation: b Severance Biomedical Science Institute and Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.|c Department of Health Sciences and Technology , SAIHST, Sungkyunkwan University School of Medicine , Seoul , Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: a Departments of Medicine , Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Korea.
authors.forename: Wenying
authors.initials: W
authors.lastname: Quan
authors.affiliation: a Departments of Medicine , Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Korea.
authors.forename: June-Chul
authors.initials: JC
authors.lastname: Lee
authors.affiliation: d Department of Life & Nanopharmaceutical Sciences and Department of Biology , Kyung Hee University , Seoul , Korea.
authors.forename: Min-Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: e Department of Pathology, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea.
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
authors.affiliation: d Department of Life & Nanopharmaceutical Sciences and Department of Biology , Kyung Hee University , Seoul , Korea.
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Bae
authors.affiliation: a Departments of Medicine , Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Korea.
authors.forename: Kyu Yeon
authors.initials: KY
authors.lastname: Hur
authors.affiliation: b Severance Biomedical Science Institute and Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.
authors.forename: Myung-Shik
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7 / Q000378:metabolism; D001835:Body Weight; D003092:Colitis / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: C502661:Atg7 protein, mouse; D016207:Cytokines; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D008055:Lipids; D017382:Reactive Oxygen Species; D000071193:Autophagy-Related Protein 7
keywords: autophagy; colitis; diabetes; inflammasome; macrophages; obesity