Adipose-specific deletion of Trx2 in mice induced excessive mitophagy, increased inflammation, and lipolysis, leading to hyperglycemia and hepatic insulin resistance.
Does administration of ROS scavenger or NF-κB inhibitor improve glucose and lipid metabolic disorders in mice with adipose-specific Trx2 deletion?
Mitophagy-mediated adipose inflammation, driven by ROS and NF-κB signaling, contributes to T2DM and hepatic insulin resistance, which can be ameliorated by ROS scavengers or NF-κB inhibitors in a mouse model.
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.
He et al. (Tue,) conducted a other in Type 2 diabetes mellitus and hepatic insulin resistance. Adipose-specific Trx2 deletion vs. Wild-type controls was evaluated. Adipose-specific deletion of Trx2 in mice induced excessive mitophagy, increased inflammation, and lipolysis, leading to hyperglycemia and hepatic insulin resistance.