Abstract 17917: Role of Glutathione S-transferase P in High Fat Diet-Induced Obesity: Dissociation of Endothelial Dysfunction from Insulin Resistance
Consumption of a high-fat diet (HFD) is associated with an increase in obesity, insulin resistance and cardiovascular disease risk. In mice fed HFD, cardiovascular dysfunction and insulin resistance precede insulin resistance in skeletal muscle and liver, suggesting that cardiovascular tissues are relatively more sensitive to dietary fat. Although cardiovascular insulin resistance is linked to an increase in mitochondrial generation of reactive oxygen species, the role of oxidative stress in obesity remains unclear. In this study, we examined the role of glutathione S-transferase P (GSTP) in HFD-induced insulin resistance and endothelial dysfunction. GSTP is the major GST isoform in murine cardiovascular tissues and catalyzes the conjugation of reactive electrophilic products generated from lipid peroxidation. To examine the role of GSTP, male wild-type (WT; C57BL/6) and GSTP-null mice were fed normal chow (NC, 12% kcal fat) or a HFD (42% kcal fat) for 12 weeks. In WT-mice HFD feeding leads to a 50 % decrease in the abundance of GSTP in the heart and the liver, indicating that dietary fat downregulates GSTP. In comparison with HFD-fed WT mice, HFD-fed GSTP-null mice gained 43% less weight (+11.7±1.1g vs +6.7±0.6g; p<0.05) and were not hyperinsulinemic (WT: NC, 0.374±0.027 ng/ml, n=12; HFD, 0.867±0.095 ng/ml, n=11, p<0.001; GSTP-null: NC, 0.423±0.037 ng/ml, n=10; HFD, 0.560±0.046 ng/ml, n=6) but had similar levels of hypercholesterolemia, hyperglycemia and HbA1c. Although HFD-fed WT mice and GSTP-null mice displayed similar insensitivity in the glucose tolerance test, HFD-fed GSTP-null mice were significantly more resistant in an insulin tolerance test compared with HFD-fed WT mice. In addition, HFD-feeding significantly impaired endothelial function (measured as acetylcholine-induced relaxation in isolated aorta) in WT mice (NC: −75±4.5%, n=10; HFD: −58.2±5.7%, n=11; p<0.05) but not in GSTP-null mice (NC: −77.4±6.5 %, n=8; HFD: −76.8±4.1%, n=7). These data indicate that despite increasing systemic insulin resistance, the deletion of GSTP limited weight gain, prevented hyperinsulinemia and preserved endothelial function during high-fat diet feeding indicating a complex and significant role of GSTP in insulin-sensitive tissues.
- © 2010 by American Heart Association, Inc.