The Role of Adipose H6PDH in Type 2 Diabetes and Obesity

脂肪 H6PDH 在 2 型糖尿病和肥胖中的作用

基本信息

批准号：
9324214
负责人：
YANJUN LIU
金额：
$ 32.29万
依托单位：
CHARLES R. DREW UNIVERSITY OF MED & SCI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324214
关键词：
Adipocytes Adipose tissue Affect Animal Experiments Blood Body Composition Body Weight CCAAT-Enhancer-Binding Proteins Cells Central obesity Coculture Techniques Corticosterone Cortisone Culture Techniques Cushing Syndrome Deposition Development Diabetes Mellitus Diabetic mouse Diet Disease Distant Endoplasmic Reticulum Energy Metabolism Ensure Enzymes Epidemic Etiology Evaluation Evolution Exhibits Fatty Acids Fatty acid glycerol esters Functional disorder Generations Genes Glucocorticoids Gluconeogenesis Glucose Glucose-6-Phosphate Glycolysis Grant Hepatocyte Hexoses High Fat Diet Homeostasis Hydrocortisone Hydroxysteroid Dehydrogenases Hyperglycemia Hyperlipidemia Hypertension Individual Inorganic Phosphate Transporter Insulin Resistance Knock-out Knockout Mice Link Lipase Lipids Lipolysis Liver Mediating Metabolic Metabolic syndrome Metabolism Molecular Mus Muscle Muscle Cells Muscle Fibers NADP Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Oxidoreductase Pathogenesis Pathway interactions Patients Peripheral Phenotype Physiological Plasma Play Production Public Health Receptor Activation Reporting Risk Rodent Model Role Signal Transduction Skeletal Muscle Small Interfering RNA Technology Tissues Transcript Transgenic Mice Transgenic Model Translating Up-Regulation Visceral Weight abdominal fat acipimox biological adaptation to stress blood glucose regulation cell growth regulation cofactor design diabetic endoplasmic reticulum stress glucose disposal hormone metabolism improved in vivo inhibitor/antagonist inorganic phosphate insulin sensitivity insulin signaling metabolic phenotype novel novel therapeutic intervention novel therapeutics overexpression prevent public health relevance treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes (T2DM) have become public health problems of epidemic proportions and much effort is being undertaken to understand the molecular mechanisms underlying the pathogenesis of these conditions to design new treatments. Obesity dramatically increases the risk of developing T2DM and patients with glucocorticoid (GC) excess (Cushing's syndrome) produce visceral obesity and diabetes, but circulating GC levels are not elevated in the vast majority of patients with typical obesity and metabolic syndrome (MS). However, many typical obesity and MS can be accounted for by abnormally increased regeneration of GCs within adipose tissue by an intracellular endoplasmic reticulum (ER) lumen-resident enzyme, 11ß-hydroxysteroid dehydrogenase (11ß-HSD1) that can generate active cortisol from inactive cortisone and thus amplifies intracellular GC action despite unaltered plasma GC levels in obesity and MS. Pre-receptor activation of GCs via 11ß-HSD1 is thus regarded as a common molecular etiology for obesity and MS. However, 11ß-HSD1 within the ER is crucially dependent on the enzyme hexose-6-phosphate dehydrogenase (H6PDH) to maintain its cofactor NADPH availability. In the ER lumen, H6PDH can metabolize glucose-6-phosphate (G6P) and generates NADPH from NADP and requires the G6P transporter to maintain its metabolic substrate G6P levels. H6PDH is thus able to couple the regulation of cellular G6P metabolism and GC signaling linked to the pathogenesis of T2DM and obesity. Indeed, we have shown that the increased adipose H6PDH expression leading to up-regulation of 11ß-HSD1 in obese diabetic mice is similar to that found in adipose tissue from T2DM patients. However, the functional consequences of altered adipose H6PDH expression are unknown. Using our unique transgenic mouse overexpression of H6PDH selectively in adipose tissue, we have observed that these mice have abnormally increased adipose corticosterone production and cellular G6P metabolism and exhibited the adverse metabolic phenotypes with hyperglycemia, visceral fat accumulation, hyperlipidemia, and insulin resistance. We thus hypothesize that adipose H6PDH plays an important role in the pathophysiology of obesity and insulin resistance, and can be manipulated to provide potential strategies for the treatment of MS. In this grant, we will explore the impact of adipose H6PDH on glucose homeostasis and insulin sensitivity in vivo using our unique existing H6PDH transgenic model. We will also directly examine the role of altered H6PDH expression in insulin signaling action through manipulation of H6PDH to regulation of cellular GC regeneration and G6P metabolism by using siRNA technology in intact mouse adipocyte cells. This will be facilitated by generation and evaluation of a H6PDH fat-specific knockout mouse. We believe that manipulating the role and impact of H6PDH on adipose function and homeostasis will provide new strategies that may translate into novel therapies for patients with T2DM and MS.

描述（由适用提供）：肥胖和2型糖尿病（T2DM）已成为流行病的公共卫生问题，并且正在努力理解这些疾病发病机理的分子机制，以设计新的治疗方法。肥胖大大增加了发展T2DM的风险，糖皮质激素（GC）超过（Cushing's综合征）患者会产生内脏肥胖和糖尿病，但是典型肥胖和代谢综合征（MS）的绝大多数患者循环GC水平并没有升高。但是，许多典型的肥胖和MS可以通过通过细胞内内质网（ER）腔内酶（ER）腔内酶的绝对增加GC在脂肪组织内的再生，11β-羟基翅目酶（11ß-Hydroxysteroid）脱氢酶（11ß-HSD1），从而产生活跃的Cortisol cortriss cortris cortristic corterivier，从而产生非活性Cortistor corterififififififififififififier cortristial corterive corterive corterive cortter Intive cortterififififififififififififififififififififififififi。肥胖和MS的血浆GC水平。因此，通过11ß-HSD1对GC的受体前激活被认为是肥胖和MS的常见分子病因。但是，ER内的11ß-HSD1基本上取决于己糖-6-磷酸酶脱氢酶（H6PDH），以维持其辅因子NADPH的可用性。在ER管腔中，H6PDH可以代谢6-磷酸葡萄糖（G6P），并从NADP产生NADPH，并要求G6P转运蛋白维持其代谢底物G6P水平。因此，H6PDH能够对细胞G6P代谢的调节和与T2DM和肥胖的发病机理相关的GC信号传导。实际上，我们已经表明，肥胖糖尿病小鼠中11ß-HSD1上调的脂肪H6PDH表达增加与T2DM患者的脂肪组织中发现的脂肪增加。但是，脂肪H6PDH表达改变的功能后果尚不清楚。利用我们在脂肪组织中选择性地选择性的H6PDH的独特的转基因小鼠过表达，我们观察到，这些小鼠的脂肪皮质酮生产和细胞G6P代谢的绝对增加，并表现出异常的不良代谢表型，具有高血糖，内脏脂肪，高脂脂肪症和胰岛素的耐药性。因此，我们假设脂肪H6PDH在肥胖和胰岛素抵抗的病理生理学中起着重要作用，并且可以操纵以为MS治疗提供潜在的策略。在这笔赠款中，我们将使用我们独特的现有H6PDH转基因模型探索脂肪H6PDH对体内葡萄糖稳态和胰岛素敏感性的影响。我们还将通过操纵H6PDH来调节细胞GC再生和G6P代谢，通过在完整的小鼠脂肪细胞中使用siRNA技术来调节细胞GC再生和G6P代谢，从而直接研究H6PDH表达改变在胰岛素信号传导作用中的作用。这将通过生成和评估H6PDH脂肪特异性敲除小鼠制备。我们认为，操纵H6PDH对脂肪功能和稳态的作用和影响将提供新的策略，这些策略可能转化为T2DM和MS患者的新型疗法。