2011 ADA Posters 1261-2041.indd - Diabetes

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& 1679-P A-769662-Mediated AMPK Activation in the Liver Reverses Hepatic Steatosis in Lipodystrophic Mice MARC FORETZ, JOCELYNE LECLERC, BENOIT VIOLLET, Paris, France AMP-activated kinase (AMPK) is a key regulator of lipid metabolism which increases fatty acid oxidation and decreases lipid synthesis. Leptin and adiponectin, two adipokines secreted by adipose tissue, activate AMPK and stimulate lipid oxidation. Lipodystrophic syndrome is characterized by loss of adipose tissue depots associated with low adipokine levels, hepatic steatosis and severe insulin resistance. We hypothesized that fatty liver in lipodystrophy may be in part explained by an alteration in AMPK activity. Inversely, pharmacological activation of AMPK in the liver may alleviate hepatic steatosis associated with lipodystrophy. We measured AMPK activity in liver from aP2-SREBP-1c mice, a lipodystrophy model transgenic mice. We found that AMPK activity was decreased by 50% and phosphorylation of acetyl-CoA carboxylase (ACC), its downstream substrate, was reduced by 40%. Moreover, hepatic fatty acid oxidation assessed by the plasma concentration of ketones bodies was decreased by 50% and hepatic triglyceride (TG) content was increased by 5-fold. The small molecule A-769662 has been identifi ed as a potent and direct activator for AMPK. Treatment of aP2-SREBP-1c mice with A-769662 for 1 week at a dose of 30 mg/kg b.i.d. increased phosphorylation of AMPK and phospho-Ser79-ACC/ACC ratio in liver. Hepatic fatty acid oxidation was completely restored. Importantly, hepatic TG and cholesterol content were decreased by 10-fold and 20%, respectively. In conclusion, AMPK activity and fatty acid oxidation were decreased in the liver of lipodystrophic mice whereas A-769662 treatment led to increased rates of fatty acid oxidation and abolished fatty liver. Our study suggests that small molecule AMPK activators may have therapeutic potential to reverse hepatic steatosis in patients with lipodystrophy or other metabolic diseases. 1680-P De Novo Lipogenesis Induced Hepatic Steatosis and Insulin Resistance Involve ER Stress but Not Infl ammation in Contrast to Lipid Oversupply LU-PING REN, STANLEY MH CHAN, XIAO-YI ZENG, ROSS D. LAYBUTT, TRISTAN J. ISELI, EDWARD W. KRAEGEN, GREGORY J. COONEY, NIGEL TURNER, JI-MING YE, Sydney, Australia, Melbourne, Australia Mitochondrial dysfunction, infl ammation and endoplasmic reticulum (ER) stress have been implicated in hepatic steatosis and insulin resistance in genetically obese and insulin resistant mice. The present study investigated the role of mitochondrial dysfunction, infl ammation and ER stress in the development of hepatic steatosis and insulin resistance due to hepatic de novo lipogenesis from a high fructose diet (HFru), compared to that of extrahepatic lipid oversupply from a high fat diet (HFat). Mice fed HFru or HFat developed marked hepatic steatosis (triglyceride increased by 3.5 and 2.4 fold, p
Integrated Physiology/ Obesity POSTERS novel long-term model indicates that diabetes contributes to progression from NASH to more end-stage liver disease. Subsequent studies will further defi ne molecular mechanisms of this process. Supported by NHMRC of Australia Project Grant #632822. Supported by: NHMRC of Australia Project Grant No. 632822 1683-P Differential Response of Mitochondrial Enzymes to Obesity and Excessive Dietary Fat Intake ELIZAVETA V. MENCHIKOVA, WAN HUANG, FREDERICO G.S. TOLEDO, ROBERT M. O’DOHERTY, BRET H. GOODPASTER, VLADIMIR B. RITOV, Pittsburgh, PA The current study was undertaken to compare the effect of obesity or excessive fat intake on specifi c activity (per mitochondria mass) of electrontransport chain (NADH-oxidase) and TCA cycle (citrate synthase (CS) that provides entrance of acetyls into TCA cycle) enzymes in human skeletal muscle and rat liver. Tissue cardiolipin (CL) content was measured as independent non-enzymatic marker of mitochondrial mass. We compared CL, NADHoxidase and CS activity in skeletal muscle biopsies from sedentary lean insulin sensitive (L, n=9, age 47±2, BMI 24±1) and sedentary obese insulin resistant (Ob, n=15, age 42±3, BMI 35±1) subjects. There is no difference in CL content in skeletal muscle from L and Ob (74±9 and 76±6 μg/mU CK, respectively). The activity of NADH-oxidase was reduced signifi cantly in Ob in comparison with L (5.63±1.59 and 2.45±0.23 U/mg CL (P=0.02) for L and Ob subjects, respectively). However, the citrate synthase activity is signifi cantly higher in obesity in comparison with lean group (35.8±3.4 and 54.5±5.3 U/mg CL (P=0.02) for L and Ob, respectively). Analysis of liver mitochondria was performed on a rodent high-fat feeding model. Five weeks of high–fat feeding in rats (n=4) induces insulin resistance, decreases specifi c NADH-oxidase activity (1.470±0.53 and 0.997±0.08 U/ mg CL for control (C) and high fat-fed (HF) rats, respectively), signifi cantly increases citrate synthase activity (19.7±2.1 and 27.4±1.4 U/mg CL (P=0.023) for C and HF rats, respectively) and slightly decreases liver cardiolipin content. We hypothesize that excessive dietary fat intake induces activation of CS (by induction of protein synthesis or by post-translational modifi cation in liver and skeletal muscle) to utilize excessive acetyl-CoA produced in beta-oxidation pathway. These data highlight that mitochondrial TCA cycle and electron transport chain enzymes respond differently to energy excess. Further investigation is needed to better understand the respective roles of specifi c mitochondrial function in obesity and insulin resistance. <strong>ADA</strong>-Funded Research 1684-P Effect of Ecdysterone on Hepatic AMP Activated Protein Kinase in Mice Fed with a High-Fat Diet ZHONG Q. WANG, YONGMEI YU, XIAN H. ZHANG, DAVID RIBNICKY, WILLIAM T. CEFALU, Baton Rouge, LA, New Brunswick, NJ Chronic nutrient overload leads to obesity and metabolic disorders, including insulin resistance and type 2 diabetes. Ecdysterone (Ecdy), specifi cally20-hydroxyecdysone, is a steroid hormone from plants). Our previous study showed that Ecdy may have anti-obesity and anti-diabetic effects, but its molecular mechanisms remain largely unknown. It is well documented AMP activated protein kinase (AMPK) plays a key role in glucose metabolism. In order to evaluate the effect of Ecdy on AMPK signaling, we examined hepatic AMPK pathway proteins in mice fed a low-fat diet (control) or high-fat diet (HFD) with or without low dose (25 mg/kg body weight, Ecdy L) or high-dose (50 mg/kg, Ecdy H) of Ecdy for 12 weeks. Body weight, fasting glucose and insulin concentrations were measured as well. At study end, no differences in body weight, food intake or energy expenditure were observed between HFD groups with or without Ecdy L, but the body weight was signifi cantly lower in Ecdy H group relative to the HFD group (P
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2011 ADA Posters 1261-2041.indd - Diabetes

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