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

• 批准号: 8743066
• 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
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743066
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Accounting; 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; Homeostasis; Hydrocortisone; Hyperglycemia; Hyperlipidemia; Hypertension; Individual; 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; 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 6-phosphate(transporter); glucose disposal; hormone metabolism; improved; in vivo; inhibitor/antagonist; inorganic phosphate; insulin sensitivity; insulin signaling; novel; novel therapeutics; overexpression; prevent; public health relevance; treatment strategy

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, 11?-hydroxysteroid dehydrogenase (11?-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 11?-HSD1 is thus regarded as a common molecular etiology for obesity and MS. However, 11?-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 11?-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（由申请人提供）：肥胖和2型糖尿病（T2DM）已成为流行病比例的公共卫生问题，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）过量（Cushing's综合征）患者会产生内脏肥胖和糖尿病，但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。 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, 11?-hydroxysteroid dehydrogenase (11?-HSD1) that can generate active cortisol from inactive cortisone and thus amplifies intracellular GC action despite肥胖和MS中未改变的血浆GC水平。因此，通过11？-HSD1对GCS的受体前激活被视为肥胖和MS的常见分子病因。但是，ER内的11个-HSD1至关重要取决于己糖-6-磷酸酶脱氢酶（H6PDH），以维持其辅助因子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11？-HSD1上调的脂肪H6PDH表达增加与T2DM患者的脂肪组织中发现相似。但是，脂肪H6PDH表达改变的功能后果尚不清楚。使用我们在脂肪组织中选择性地对H6PDH的独特转基因小鼠过表达，我们观察到，这些小鼠异常增加脂肪皮质酮的生产和细胞G6P代谢，并表现出具有不良代谢表型，具有高血糖症，内脏脂肪累积，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脂肪特异性基因敲除小鼠来促进。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。