Insulin Resistance in Insulin-Resistant and Diabetic Hamsters (Mesocricetus auratus) Is Associated with Abnormal Hepatic Expression of Genes Involved in Lipid and Glucose Metabolism

Fat-induced hepatic insulin resistance (FIHIR) in obesity induced by high-fat diet leads to ectopic lipid accumulation and may contribute to the pathogenesis of type 2 diabetes. We examined the alterations in hepatic gene expression involved in FIHIR by using obese insulin-resistant and diabetic hamsters that received high-fat diet with or without low-dose streptozotocin. Microarray analysis and confirmatory real-time RT-PCR indicated that increased mRNA levels of sterol regulatory element-binding proteins (SREBPs) and decreased mRNA levels of liver X receptor (LXRα) and peroxisome-proliferator–activated receptor (PPARα) occurred in FIHIR in insulin-resistant and diabetic hamsters. Expression levels of hepatic LXRα, SREBPs, and PPARα differed significantly between insulin-resistant and diabetic hamsters. Expression of LXRα, SREBPs, and PPARα all change in FIHIR associated with hepatic lipid accumulation in insulin-resistant and diabetic hamsters in which disease is induced by high-fat diet and streptozotocin injection.Abbreviations: Acaa2, acetyl coenzyme A acyltransferase 2; Acadm, medium-chain acyl coenzyme A dehydrogenase; ACC, acetyl coenzyme A carboxylase; Acox, acyl coenzyme A oxidase; Cpt1, carnitine–palmitoyl transferase 1; CYP7A1, cholesterol 7α hydroxylase; FAS, fatty acid synthase; FIHIR, fat-induced hepatic insulin resistance; Gck, glucokinase; G6Pase, glucose-6-phosphatase; HDL, high-density lipoprotein; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A; IRS, insulin receptor substrate; LDL, low-density lipoprotein; LDLR, LDL receptor; LXR, liver X receptor; PEPCK, phosphoenolpyruvate carboxykinase; PGC1α ,peroxisome-proliferator–activated receptor γ coactivator 1α; PPAR, peroxisome-proliferator–activated receptor; SCD1, stearoyl coenzyme A desaturase 1; SREBP, sterol regulatory element-binding proteinInsulin resistance plays a critical role in the development of type 2 diabetes.^7,9,27 However, the underlying mechanisms remain poorly understood. Obesity induced by a diet high in saturated fat and cholesterol is the most common and important environmental factor for the insulin resistance of type 2 diabetes.^2,6 A potential mechanism is ectopic lipid accumulation caused by abnormalities in lipid metabolism in insulin-sensitive tissues (so-called ‘lipotoxicity’), thereby leading to fat-induced insulin resistance.^14,24 The liver, an insulin-sensitive tissue, plays a unique role in controlling carbohydrate, lipid, and energy metabolism by maintaining glucose and lipid concentrations within a normal range. Hepatic insulin resistance contributes greatly to the development of the hyperglycemia, dyslipidemia, hepatic steatosis, and systemic insulin resistance in type 2 diabetes mellitus.^13,20 Therefore, the mechanisms involved in hepatic insulin resistance, especially FIHIR are a prerequisite to understand pathogenesis of obesity-related type 2 diabetes.The genetic susceptibility for diabetes and many characteristic features of lipid metabolism are similar between hamsters and human.²⁸ We previously developed obese insulin-resistant and type 2 diabetic hamster models^1,12,16 to study the pathophysiologic features and natural history of obesity-related insulin resistance and type 2 diabetes. Microarray technology is a powerful tool to decipher the complex gene expression profiles associated with various diseases. In the present study, we used microarray technology to determine identify alterations in hepatic gene expression and to explore molecular mechanisms involved in FIHIR in insulin-resistant and type 2 diabetic hamsters. Understanding the gene expression patterns involved in FIHIR in obese insulin-resistant and type 2 diabetic states may provide new targets for dietary or pharmacologic interventions.