Therapeutic strategies to induce browning of white adipose tissue

摘要 肥胖已经达到了大流行的程度，这导致了代谢综合征的发展， 包括2型糖尿病和心血管疾病在内的一组疾病。肥胖症的流行 以惊人的速度增长，需要新的治疗方法。仅改变生活方式，如节食 和锻炼，并不足以对抗这些疾病。过多的卡路里摄入导致迅速膨胀 脂肪细胞导致脂肪毒性副作用，包括异位脂肪堆积和胰岛素抵抗。 肥胖白色脂肪组织(WAT)经历实质性重塑，包括渗透 巨噬细胞和纤维化。改建Wat也是有益的，并符合以下条件 增强胰岛素敏感性，减少炎症。使小鼠暴露在寒冷中或用 不同的药理试剂，如PPARγ激动剂，可以诱导WAT的褐变，包括 募集的棕色样脂肪细胞称为米色和脆性细胞。除了为仓库提供 产热细胞，棕色有可能以与瘦身相关的方式重塑肥胖的Wat 表型包括分泌“健康的”脂肪因子。我们的建议是确定新的途径 而安全和特异地激活PPARγ的策略可能是诱导 米色/褐褐色脂肪细胞。数以百万计的人已经服用PPARγ配体(文迪雅和Actos)来治疗他们的 肥胖相关的胰岛素抵抗。人们普遍认为，这些开发区的主要作用地点是 脂肪组织。尽管TZD是非常有效和强大的胰岛素增敏剂，但它们充满了 有害的副作用。其他人和我们的研究表明，针对特定的翻译后 PPARγ的修饰是一种避开PPARγ激动剂的有害影响的方法，同时保留了 胰岛素增敏活性。我们最近的研究表明，这一建议所基于的罗斯科维汀是一种 CDK抑制剂有效地使Wat变成棕色，并保护小鼠免受饮食诱导的肥胖和胰岛素的影响 抵抗。我们假设罗斯科沃廷通过翻译后修饰Wat PPARγ，这样做克服了肥胖的有害影响。我们提出了四个目标来测试这一点 假设：1.追踪罗可维汀处理小鼠所诱导的米色/褐褐色脂肪细胞的来源。2. 确定罗斯科维汀是否能阻止肥胖引起的肌成纤维细胞的扩张和激活。3. 确定并描述与 小鼠脂肪细胞中PPARγ的磷酸化(S112A/S273A)缺陷形式。4.确定是否 修饰的PPARγ在脂肪库中的表达诱导水褐变并保护动物免受日粮污染. 诱导性肥胖和纤维化。这些目标的成功实现将为我们提供对途径的新见解 调节米色/褐煤AT的形成，从而促进我们对如何治疗靶点的理解 用于治疗人类肥胖的脂肪组织。

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.