Abstract 1649: Apoptosis Signal-Regulating Kinase 1 Plays a Pivotal Role in Obesity-Induced Vascular and Metabolic Dysfunction
Background : Apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, plays a key role in oxidative stress-induced cellular responses. However, nothing is known about the role of ASK1 in obesity-induced vascular and metabolic dysfunction.
Methods and Results: To examine the potential role of ASK1 in high fat-induced obesity, diabetes and vascular dysfunction, we compared the effect of a high-fat diet (HFD) between ASK1-deficient (ASK1-/-) mice and control C57BL/6J wild-type (WT) mice. There was no significant difference in the intake of HFD between ASK1-/- and WT mice. Compared with a normal-fat diet, 12 weeks of HFD treatment in WT mice caused a statistically significant increase in body weight (+164%), liver weight (+242%) characterized by fatty liver, fat storage (mesenteric plus perirenal fat tissue; +396%) and serum leptin levels (+382%), and also significantly decreased serum adiponectin levels (−12%; P<0.01). Furthermore, HFD in WT mice induced remarkable insulin resistance and diabetes, as shown by the increase in HOMA-IR (homeostasis model assessment of insulin resistance), and impaired glucose tolerance estimated by glucose tolerance tests (GTTs) and insulin tolerance tests (ITTs). On the other hand, ASK1-/- mice fed HFD exhibited much less body weight (p<0.01), liver weight gain (p<0.01), adiposity (p<0.01), and serum leptin levels (p<0.01) than WT mice fed HFD, and also higher serum adiponectin (p<0.05) than WT mice fed HFD. HFD-induced insulin resistance and diabetes was much milder in ASK1-/- mice than WT mice, as indicated by the difference in HOMA-IR (p<0.01), ITTs (p<0.05) and GTTs (p<0.05). Moreover, HFD treatment significantly impaired vascular endothelium-dependent relaxation (EDR) to acethylcholine in WT mice, while the impairment of vascular endothelial function by HFD was much less in ASK1-/- mice than in WT mice (p<0.01).
Conclusion: Our work provided the first evidence that ASK1 activation plays the key role in HFD-induced obesity, insulin resistance, diabetes and vascular endothelial dysfunction. Thus, we propose that ASK1 may be the novel therapeutic target for vascular diseases in metabolic syndrome.