Therapeutic strategies to induce browning of white adipose tissue

总结 肥胖已经达到了流行病的比例，导致代谢综合征的发展， 包括2型糖尿病和心血管疾病在内的一组疾病。肥胖症的流行是 以惊人的速度增加，需要新的治疗方法。生活方式的改变，如饮食 和锻炼，不足以对抗这些疾病。过量的热量摄入会导致 导致脂毒性副作用，包括异位脂肪积聚和胰岛素抵抗。 肥胖的白色脂肪组织（WAT）经历实质性的重塑，包括 巨噬细胞和纤维化。WAT的重塑也是有益的，并且与以下条件相吻合： 增强胰岛素敏感性和减少炎症。将小鼠暴露在寒冷中或用 各种药理学试剂如PPARγ激动剂诱导WAT的布朗宁，其包括 棕色样脂肪细胞的募集，称为米色和棕色细胞。除了为仓库提供 产热细胞，布朗宁有可能重塑肥胖WAT的方式与瘦 表型包括分泌“健康”脂肪因子。我们的建议是， 安全和特异性激活PPARγ的策略可能是诱导 米色/米色脂肪细胞。数以百万计的人已经服用了PPARγ配体（文迪雅和Actos）来治疗他们的疾病。 肥胖相关的胰岛素抵抗公认的是，这些TZD的主要作用部位是 脂肪组织尽管TZDs是非常有效和强效的胰岛素增敏剂，但它们充满了 有害的副作用其他人和我们的研究表明，靶向特定的翻译后 修饰的PPARγ是一种手段，以规避有害影响的PPARγ激动剂，同时保留 胰岛素增敏活性。我们最近的研究表明，这一建议的基础上，roscovitine，一个 CDK抑制剂有效地使WAT褐变并保护小鼠免受饮食诱导的肥胖（DIO）和胰岛素 阻力我们推测，罗斯科伏汀棕色WAT通过翻译后修饰 PPARγ，并在这样做克服了肥胖的有害影响。我们提出了四个目标来检验这一点 假设：1.追踪用roscovitine处理小鼠诱导的米色/棕色脂肪细胞的起源。2. 确定roscovitine是否可以防止肥胖诱导的肌成纤维细胞的扩增和激活。3. 鉴定和表征与一种蛋白相互作用的共调节因子（共激活因子和共抑制因子）， 在小鼠脂肪细胞中的磷酸化（S112 A/S273 A）缺陷形式的PPARγ。4.确定是否 脂肪库中修饰的PPARγ的表达诱导WAT的布朗宁，并防止饮食- 导致肥胖和纤维化。这些目标的成功完成将为路径提供新的见解 调节beige/brite AT的形成，从而促进我们对如何治疗靶向 脂肪组织用于治疗人肥胖症。

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.