Hyperglycemia drives the alteration of oxidative stress response in HSCs. (A-B) Comparison of leptin-dependent db and ob mouse models of obesity. (A) Bodyweight and nonfasting blood glucose of 4-month-old db and ob mice compared with their respective littermate controls (n = 9-21). (B) Mean percentage ± standard deviation (SD) of db and ob HSC-SLAMs presenting FOXO nuclear localization after 30 minutes of in vitro treatment with medium or ROS (H₂O₂: 100 µM) (n = 5 with 50 cells measured per condition per experiment). (C-H) Analyses of (C-E) a polygenic mouse model of obesity (MS-NASH/male) and (F-H) a mouse model of type I diabetes (Ins2^Akita/male). (C,F) Mean bodyweight and nonfasting blood glucose ± SD of 4-month-old MS-NASH and Ins2^Akita male mice compared with their respective littermate controls (n = 2-4). (D,G) Representative FACS histogram showing levels of intracellular ROS detected by DCFDA in HSC-SLAMs isolated from MS-NASH and Ins2^Akita mice compared with age- and sex-matched littermate and db control (representative of 2-3 independent experiments). (E,H) Mean percentage ± SD of MS-NASH and Ins2^Akita HSC-SLAMs presenting FOXO nuclear localization after 30 minutes of in vitro treatment with medium or ROS (H₂O₂: 100 µM) (n = 2-4, with 50 cells measured per condition per experiment). Two-way ANOVA with Sidak’s post hoc test, except for panels C and F for which unpaired, 2-tailed Student t tests were used; **P < .01; ***P < .001; ****P ≤ .0001.