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

The Journal of experimental medicine (2020-12-15)
Feng He, Yanrui Huang, Zhi Song, Huanjiao Jenny Zhou, Haifeng Zhang, Rachel J Perry, Gerald I Shulman, Wang Min
RÉSUMÉ

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.

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Roche
Kit de détection in situ de la mort cellulaire, fluorescéine, sufficient for ≤50 tests, suitable for detection
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Adenosine 5′-triphosphate (ATP) Bioluminescent Assay Kit, for ATP quantitation
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BMS-345541, ≥98% (HPLC), powder