A thrifty microRNA in insulin resistance and Type 2 diabetes

胰岛素抵抗和 2 型糖尿病中节俭的 microRNA

• 批准号: 9364401
• 负责人: ANDERS M NAAR
• 金额: $ 36万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9364401
• 关键词: Address; Adult; Agriculture; Albumins; Animals; Antisense Oligonucleotides; Blood Chemical Analysis; Cardiovascular Diseases; Cell Culture Techniques; Cholesterol; Consumption; Creatinine; Cytomegalovirus; Data; Development; Diabetes Mellitus; Diet; Disease; Disease model; Dose; Energy Intake; Energy Metabolism; Enzymes; Etiology; Euglycemic Clamping; Famines; Fatty acid glycerol esters; Food; Functional disorder; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Translation; Genetic study; Genomics; Glucose; Hepatic; High Density Lipoproteins; Histologic; Homeostasis; Human; Human Genetics; Human Genome; Hypertension; Hypertriglyceridemia; Impairment; In Vitro; Individual; Insulin; Insulin Resistance; Integration Host Factors; Investigation; Kidney; Knockout Mice; Lactase; Link; Lipids; Liver; Low-Density Lipoproteins; Medicine; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic syndrome; Metabolism; MicroRNAs; Milk; Modality; Molecular; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obese Mice; Obesity; Pathway interactions; Population; Prevention; Protein Inhibition; Recovery; Regimen; Regulation; Rodent Model; Role; Science; Skeletal Muscle; Staining method; Stains; Testing; Therapeutic; Time; Tissues; Toxic effect; Translational Research; Translations; Triglycerides; Visceral; base; blood glucose regulation; blood lipid; cholesterol control; genetic association; genome wide association study; glucose production; glucose tolerance; glucose uptake; improved; in vivo; insight; insulin sensitivity; insulin tolerance; lipid metabolism; mRNA Transcript Degradation; metabolomics; mouse model; non-alcoholic fatty liver; novel; novel therapeutics; precision medicine; programs; sedentary lifestyle; subcutaneous; therapeutic target; transcription factor; transcriptome sequencing; translational medicine; validation studies

Project Summary/Abstract The metabolic syndrome (MetS), a constellation of conditions and disorders including obesity, insulin resistance/abnormal glucose regulation, nonalcoholic fatty liver disease (NAFLD), elevated circulating LDL- C/HDL-C ratios and triglycerides, and hypertension, is rapidly increasing world-wide and is associated with more severe diseases such as type 2 diabetes and cardiovascular disease. However, the genetic and molecular contributions to the etiology of MetS remain unclear. We recently discovered microRNAs (miR- 33b/a) as key regulators of cholesterol/lipid homeostasis. We have now employed genome-wide association studies (GWAS) to uncover the miR-128-1 microRNA as linked to cholesterol/lipid abnormalities, obesity, type 2 diabetes and recent human positive selection. Our preliminary in vitro and in vivo studies in mice have confirmed that miR-128-1 exerts profound effects on metabolic homeostasis. We propose here to test the hypothesis that miR-128-1 represents a central regulator of mammalian energy metabolism, and that human evolutionary adaptation to feast/famine cycles in ancient times led to increased miR-128-1 activity promoting energy storage in certain human populations. While beneficial in times of famine, elevated miR-128-1 activity/levels in present times with profound food abundance in the developed world could contribute to metabolic diseases such as obesity and type 2 diabetes. Both in vitro cell culture and in vivo studies in mouse metabolic disease models (e.g., DIO, ob/ob mice) with antisense targeting of miR-128-1, as well as miR-128-1 KO mice will provide critical mechanistic insights into the role of miR-128-1 in targeting pathways guiding metabolic homeostasis, and whether this microRNA may be suitable for therapeutic targeting to improve prevalent metabolic disorders such as obesity and type 2 diabetes.

项目总结/摘要 代谢综合征（MetS）是一组疾病和病症，包括肥胖、胰岛素抵抗、糖尿病 抵抗/异常葡萄糖调节，非酒精性脂肪肝（NAFLD），循环LDL- C/HDL-C比值和甘油三酯以及高血压在全球范围内迅速增加， 更严重的疾病，如2型糖尿病和心血管疾病。然而，基因和 MetS病因学的分子贡献仍不清楚。我们最近发现了microRNAs（miR- 33 b/a）作为胆固醇/脂质稳态的关键调节剂。我们现在使用了全基因组关联 研究（GWAS）揭示miR-128-1 microRNA与胆固醇/脂质异常、肥胖、 2型糖尿病与近期人类正选择。我们的初步体外和体内小鼠研究 证实了miR-128-1对代谢稳态发挥深远的影响。我们建议在这里测试 假设miR-128-1代表哺乳动物能量代谢的中心调节因子，而人类 在古代，对盛宴/饥荒周期的进化适应导致miR-128-1活性增加， 在某些人群中储存能量。虽然在饥荒时期有益，但miR-128-1 目前发达国家粮食丰富的活动/水平可能有助于 代谢性疾病，如肥胖症和2型糖尿病。体外细胞培养和小鼠体内研究 代谢疾病模型（例如，DIO，ob/ob小鼠）与miR-128-1以及miR-128-1的反义靶向 KO小鼠将为miR-128-1在靶向途径中的作用提供关键的机制见解， 代谢稳态，以及这种microRNA是否适用于治疗靶向，以改善 流行的代谢紊乱，如肥胖症和2型糖尿病。