Abstract 500: Low Aldehyde Dehydrogenase 2 (ALDH2) Potentiates Obesity in Leptin Receptor Mutant Mice

Abstract

Obesity aggravates type 2 diabetes and thus cardiometabolic complications. Aldehyde dehydrogenase 2 (ALDH2), a cardiac mitochondrial enzyme is known to be cardioprotective. ALDH2*2 is the most common genetic mutation in East Asians (~800 million carriers), which causes a low ALDH2 activity. We hypothesize that ALDH2*2 mutation aggravates obesity and diabetes in leptin receptor deficient db/db mice and consequentially cardiometabolic complications. To test our hypothesis, we cross db/db mice with ALDH2*2 knock-in mutant mice. We obtained a new breed of mice which had leptin receptor mutation and ALDH2*2 mutant gene. We termed this mice as ALDH2*2-Fat. The body weight gain of ALDH2*2-Fat mice was extremely faster than their non-obesity littermates (ALDH2*2-Lean, the mice only carrying ALDH2*2 mutant gene). At 30 weeks old, the body weights of ALDH2*2-fat mice (84.15±6.75 g) was 2.88 folds higher than ALDH2*2-Lean mice (29.32±3.75 g, p<0.001). Fasting blood glucose and serum insulin concentration were higher in ALDH2*2-Fat mice than ALDH2*2-Lean mice (blood glucose: 506.20±88.27 vs. 192.83±21.32 mg/dl, p<0.001; insulin: 13.94±6.28 vs. 2.46±0.58 ng/ml, p<0.001 respectively). Echocardiographic measurements revealed a progressive cardiac dysfunction in ALDH2*2-Fat mice (Fractional shortening, 48.00±3.17 vs. 56.90±3.11 % at 6 months, p<0.05, and 39.11±7.50 vs. 56.98±1.55 % at 9 months, p<0.01). Body temperatures were significantly lower in ALDH2*2-Fat mice (35.5±0.94 vs. 38.86±0.49 °C, p<0.01). The interscapular brown adipose tissues in ALDH2*2 fat mice were shrunk to invisible at 9 months old. Western-blotting found a decreased PGC-1 α and increased PPAR-γ expression in white adipose tissues from ALDH2*2-fat mice. Cultured primary bone marrow cells showed a significantly decrease in colony forming units in ALDH2*2-Fat mice (7.67±4.50 vs., 26.33±3.33 p<0.05). Under adipogenic medium, the adipocytes differentiation was increased in ALDH2*2 fat mice. In conclusion, low ALDH2 activity aggravates obesity and consequentially cardiometabolic complications in leptin receptor deficiency-induced obesity and diabetes.