Transcription profiling of adipose tissue, liver, skeletal muscle, and pancreatic islets from nondiabetic and diabetic obese mice to understand susceptibility to diabetes

Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes. Diabetes 52:688--700, 2003 Experiment Overall Design: Four B6-ob/ob and four BTBR-ob/ob male mice at 14 weeks of age were used in the microarray study. RNA samples from two individuals were pooled for each tissue, and each pooled RNA sample was applied to an Affymetrix MGU74AV2 array. Because of the scarcity of islets in the BTBR-ob/ob mice, 4 additional mice were pooled to obtain islet RNA from these animals. Sixteen MGU74Av2 arrays (2 strains X 4 tissues X 2 replicates = 16 arrays) were used to monitor the expression level of ~12,000 genes or ESTs.肥胖是2型糖尿病发生的重要危险因素。我们此前已报道，肥胖（ob/ob）小鼠的脂肪组织中，成脂基因的表达水平呈下调状态。BTBR小鼠品系在发生遗传性肥胖时易患糖尿病，而C57BL/6J（B6）品系则具有糖尿病抵抗性。我们采用DNA微阵列与逆转录聚合酶链式反应（RT-PCR）技术，对比分析了BTBR-ob/ob与B6-ob/ob小鼠脂肪组织、肝脏、骨骼肌及胰岛中的基因表达谱。本研究结果如下：1）糖尿病小鼠的脂肪组织中，参与炎症反应的基因表达水平显著上调；2）与糖尿病抵抗性肥胖小鼠相比，糖尿病易感小鼠的脂肪组织中成脂基因的表达水平更低，且随糖尿病病程进展持续降低；3）糖尿病抵抗性肥胖小鼠的肝脏中，成脂酶的表达水平升高，同时肝脏甘油三酯含量大幅升高；4）糖异生相关基因的表达在糖尿病前期受到抑制，但在糖尿病发病时未出现该变化；5）原本不在骨骼肌和胰岛中表达的基因，在糖尿病小鼠的上述组织中出现了表达。我们提出假说：肝脏成脂能力的增强可使B6-ob/ob小鼠免于发生2型糖尿病。*Diabetes* 52:688–700, 2003 实验整体设计：本次微阵列研究共使用4只14周龄的雄性B6-ob/ob小鼠与4只同周龄雄性BTBR-ob/ob小鼠。每个组织取2只个体的RNA样本进行混合，每份混合RNA样本均应用于Affymetrix MGU74AV2基因芯片。由于BTBR-ob/ob小鼠的胰岛组织取材量稀少，我们额外收集了4只该品系小鼠的胰岛以获取足量的RNA样本。本次研究共使用16张MGU74Av2芯片（2个品系 × 4种组织 × 2次重复 = 16张芯片），用于检测约12000个基因或表达序列标签（EST）的表达水平。