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- Title
The Synthetic Polyphenol and AMPK Activator, S17834, Improves Diet-Induced Obesity, Insulin Resistance, Hyperlipidemia, and Atherosclerosis in LDL Receptor Deficient Mice.
- Authors
Zang, Mengwei; Xu, Shanqin; Hou, Xiuyun; Maitland-Toolan, Karlene A.; Jiang, Bingbing; Wierzbicki, Michel; Verbeuren, Tony J.; Cohen, Richard A.
- Abstract
Our recent studies show that the synthetic polyphenol, S 17834, stimulates AMP-activated protein kinase (AMPK) more potently than resveratrol or metformin. Stimulation of AMPK by S17834 was shown to attenuate high glucose-induced lipid accumulation in HepG2 cells, as well as to be associated with a reduction in hepatic and serum lipids, and atherosclerosis in type 1 diabetic LDL receptor deficient (LDLR-/-) mice. To determine the effect of S17834 in obesity-induced insulin resistance and type 2 diabetes, LDLR-/- mice were fed a high fat, high sucrose (HFHS) diet for 16 weeks. Compared with normal chow, body weight gain increased ∼3-fold, and insulin resistance index, as determined by the homeostasis model assessment for insulin resistance (HOMAIR), was increased ∼2.5-fold. Hepatic steatosis caused by the HFHS diet was accompanied in the liver by decreased phosphorylation of AMPK and the AMPK downstream effector, acetyl CoA carboxylase (ACC) compared with chow fed mice. The HFHS diet caused a ∼2-fold increase in plasma cholesterol levels as well as a 4-fold increase in oil red O stained atherosclerotic lesions in aortic mot cross sections. S17834 administration (130 mg/kg/day, 16 weeks) significantly protected mice against diet-induced obesity and systemic insulin resistance. Treatment with S 17834 was accompanied by increased AMPK and ACC phosphorylation in the liver and improvement in hepatic steatosis. S17834 also significantly decreased plasma cholesterol levels and attenuated the development of aortic atherosclerotic lesions. These data show that protection afforded by S17834 from the exaggerated hyperlipidemia and vascular disease caused by type 1 diabetes extends to type 2 diabetes in LDLR-/- mice. Improvements in body weight, insulin resistance, hepatic steatosis, hyperlipidemia, and atherosclerosis may be attributed to the ability of the polyphenol to stimulate AMPK as demonstrated here to occur in the mouse liver. Activation of AMPK by polyphenols, like S17834, represents a major new avenue for treatment of hyperlipidemia and vascular disease in both type 1 and type 2 diabetes.
- Subjects
POLYPHENOLS; ADENOSINE monophosphate; PROTEIN kinases; OBESITY; INSULIN resistance; HYPERLIPIDEMIA; ATHEROSCLEROSIS; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA192
- ISSN
0012-1797
- Publication type
Article