Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance

• Published in: The Journal of experimental medicine Vol. 218; no. 3
• Main Authors: He, Feng, Huang, Yanrui, Song, Zhi, Zhou, Huanjiao Jenny, Zhang, Haifeng, Perry, Rachel J., Shulman, Gerald I., Min, Wang
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.03.2021
• Subjects: Adipocytes - metabolism; Adipocytes - ultrastructure; Adipose Tissue - pathology; Animals; Diabetes Mellitus, Type 2 - pathology; Diet, High-Fat; Energy Metabolism; Fatty Liver - pathology; Gene Deletion; Gene Targeting; Gluconeogenesis; Homeostasis; Humans; Hyperglycemia - complications; Hyperglycemia - pathology; Inflammation - pathology; Insulin Resistance; Lipogenesis; Liver - pathology; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitophagy; NF-kappa B - metabolism; Oxidative Stress; Phenotype; Reactive Oxygen Species - metabolism; Sequestosome-1 Protein; Signal Transduction; Thioredoxins - metabolism
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20201416

White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB–dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.