Therapeutic strategies to induce browning of white adipose tissue

诱导白色脂肪组织褐变的治疗策略

• 批准号: 9980890
• 负责人: STEPHEN ROBERT FARMER
• 金额: $ 41.25万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-19 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980890
• 关键词: Adipocytes; Adipose tissue; Agonist; Angiogenic Factor; Biological; Blood Vessels; Blood flow; Brown Fat; CYC 202; Calories; Cardiovascular Diseases; Catecholamines; Cells; Consumption; Cyclin-Dependent Kinase Inhibitor; Data; Deacetylation; Development; Diet; Dietary Fats; Disease; Energy Intake; Energy Metabolism; Event; Extracellular Matrix Proteins; FGF21 gene; Fatty acid glycerol esters; Fibrosis; Genes; Goals; Health Expenditures; Human; Hypertrophy; Hypoxia; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Investigation; Knowledge; Laboratories; Life; Life Style Modification; Ligands; Metabolic syndrome; Metabolism; Methods; Mitochondria; Mus; Myofibroblast; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Outcome; PPAR gamma; Pathway interactions; Pharmacology; Phenotype; Phosphorylation; Physiological; Post-Translational Protein Processing; Process; Production; Protein Dephosphorylation; Publishing; SIRT1 gene; Series; Site; Suggestion; Testing; Therapeutic; Thiazolidinediones; Thinness; United States; Vascular Endothelial Growth Factors; Work; adipokines; bariatric surgery; base; combat; design; diet and exercise; enhancing factor; genetic corepressor; human data; inhibitor/antagonist; insight; insulin sensitivity; insulin sensitizing drugs; macrophage; novel; novel therapeutics; pandemic disease; prevent; progenitor; programs; recruit; response; roscovitine; rosiglitazone; side effect; therapeutic target

SUMMARY Obesity has reached pandemic proportions contributing to the development of the metabolic syndrome, a group of disorders that include type 2-diabetes and cardiovascular disease. The obesity epidemic is increasing at an alarming rate and new therapies are needed. Lifestyle modifications alone, such as diet and exercise, are not sufficient to combat these diseases. Excess caloric intake causes the rapid expansion of adipocytes leading to lipotoxic side effects, including ectopic fat accumulation and insulin resistance. Obese white adipose tissue (WAT) undergoes substantial remodeling which includes infiltration of macrophages and fibrosis. Remodeling of WAT can also be beneficial and coincide with conditions that enhance insulin sensitivity and reduce inflammation. Exposure of mice to the cold or treating them with various pharmacological agents such as PPARγ agonists induce browning of WAT, which include recruitment of brown-like adipocytes referred to as beige and brite cells. Besides supplying the depot with thermogenic cells, browning has the potential to remodel obese WAT in ways associated with a lean phenotype including secretion of “healthy” adipokines. It is our suggestion that identifying novel pathways and strategies to safely and specifically activate PPARγ is perhaps the most efficacious way to induce beige/brite adipocytes. Millions of individuals already take PPARγ ligands (Avandia and Actos) to treat their obesity-related insulin resistance. It is well accepted that the principal site of action of these TZDs is adipose tissue. Even though the TZDs are very effective and potent insulin sensitizers they are fraught with harmful side effects. Studies by others and us have shown that targeting specific posttranslational modifications of PPARγ is a means to circumvent the harmful effects of PPARγ agonists while retaining the insulin sensitizing activity. Our recent study on which this proposal is based demonstrated that roscovitine, a CDK inhibitor potently browned WAT and protected mice from diet-induced obesity (DIO) and insulin resistance. We hypothesize that roscovotine browns WAT through post-translational modifications of PPARγ and in doing so overcomes the harmful effects of obesity. We propose four aims to test this hypothesis: 1. Trace the origin of beige/brite adipocytes induced by treatment of mice with roscovitine. 2. Determine whether roscovitine prevents obesity-induced expansion and activation of myofibroblasts. 3. Identify and characterize the co-regulators (coactivators and corepressors) interacting with a phosphorylation (S112A/S273A) deficient form of PPARγ in adipocytes in mice. 4. Determine whether expression of the modified PPARγ in adipose depots induces browning of WAT and protects against diet- induced obesity and fibrosis. Successful completion of these aims will provide novel insights into pathways regulating beige/brite AT formation, thus advancing our understanding of how to therapeutically target adipose tissues for the treatment of human obesity.

概括 肥胖已经达到了大流行比例，导致了代谢综合征的发展，一个 包括2型糖尿病和心血管疾病的疾病组。肥胖流行是 需要以惊人的速度增加，需要新的疗法。仅生活方式改变，例如饮食 运动和运动不足以打击这些疾病。过量热量摄入会导致快速扩张 导致脂肪毒性副作用的脂肪细胞，包括生态脂肪的积累和胰岛素抵抗。 肥胖的白脂肪组织（WAT）经历了重大的重塑，包括渗透 巨噬细胞和纤维化。 WAT的重塑也可能是有益的，并且与 增强胰岛素敏感性并降低感染。小鼠暴露于寒冷或对它们进行治疗 各种药物，例如诱导WAT褐变的PPARγ激动剂，其中包括 募集棕色脂肪细胞称为米色和麸皮细胞。除了向存款提供 热细胞，褐变有可能以瘦肉相关的方式重塑肥胖 表型，包括分泌“健康”脂肪因子。我们的建议是识别新的途径 安全和专门激活PPARγ的策略可能是诱导最有效的方法 米色/Brite脂肪细胞。数以百万计的人已经服用PPARγ配体（Avandia和Acts）来治疗其 肥胖相关胰岛素抵抗。这些TZD的主要行动部位是 脂肪组织。即使TZD非常有效且潜在的胰岛素传感器，但它们还是被赋予的 有害的副作用。他人和美国的研究表明，针对特定翻译后的研究 PPARγ的修饰是绕过PPARγ激动剂的有害作用的一种手段 胰岛素敏化活性。我们最近对该提案所基于的研究表明，Roscovitine，一个 CDK抑制剂可能呈褐色的WAT，并保护小鼠免受饮食诱导的肥胖症（DIO）和胰岛素 反抗。我们假设Roscovotine Browns Wats通过后翻译后修饰 PPARγ并这样做可以克服肥胖的有害作用。我们提出了四个目标来测试这一点 假设：1。通过用roscovitine治疗小鼠诱导的米色/Brite脂肪细胞的起源。 2。 确定roscovitine是否可以防止肥胖引起的膨胀和肌纤维细胞的激活。 3。 识别和表征共同调节器（共激活因子和核心量）与A相互作用 小鼠脂肪细胞中PPARγ缺乏磷酸化（S112A/S273A）。 4。确定是否 修饰的PPARγ在脂肪沉积中的表达会诱导WAT褐变，并防止饮食 诱导肥胖和纤维化。这些目标的成功完成将为途径提供新颖的见解 在形成时调节米色/麸皮，从而促进我们对如何治疗靶向的理解 脂肪组织治疗人肥胖。