Figure 8.

Inhibition of NF-κB activity ameliorates T2DM in Trx2^ADKO mice. 6-wk-old male Trx2^ADKO and WT mice were treated with 60 mg/kg BMS-345541 by i.p. injection once every 2 d for 8 wk. (A and B) Body weight (A) and fasting blood glucose levels (B) in WT and Trx2^ADKO mice with or without BMS-345541 treatment (n = 8) at the indicated ages. (C) Representative images of BODIPY staining showing liver lipid deposition of mice at 14 wk of age. Scale bars, 50 µm. (D and E) Liver TG content and serum TG level were measured. n = 6. (F) Immunoblot analysis of eWAT tissues from mice at 14 wk of age. Protein levels were quantified and presented as fold changes by taking WT as 1.0. n = 3 mice for each group. (G) Representative transmission electron micrographs of eWAT sections from mice at 14 wk of age (six images/mouse, n = 3 mice/group). Asterisks indicate LDs. Arrowheads indicate mitochondria. Scale bars, 0.5 µm. (H and I) Serum cytokines TNF-α and IL-6 proteins were measured by ELISA kits (n = 8). (J) ATP content of mitochondria isolated from eWAT of mice at 14 wk of age (n = 8). (K and L) Serum levels of NEFA (K) and adiponectin (L) of 14-wk-old mice (n = 8). Quantitative data are presented as mean ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001 versus the indicated comparisons. Significance was assessed by one-way ANOVA followed by Tukey’s post hoc test. (M) A schematic diagram summarizing our findings that Trx2 deficiency promotes severe mitophagy via mitochondrial ROS/NF-κB/p62 signaling, which contributes to hepatic insulin resistance related T2DM (see text for details). N, nucleus; DHAP, dihydroxyacetonephosphate. TAG, triacylglycerol; VLDL, very low-density lipoprotein.