Endoplasmic Reticulum Stress, Brain and Obesity

肥胖是导致衰弱疾病的主要原因，如2型糖尿病、心血管疾病 疾病、高血压、肾脏疾病、非酒精性脂肪性肝炎(NASH)，所有这些都会降低生活质量 以及寿命。尽管在开发减肥药物方面做出了巨大的努力，但目前 现有的药物对体重的影响很小(在3-10%的范围内)，而且大多数都是 由于副作用而退出市场。因此，迫切需要安全有效的 肥胖症的医疗治疗 瘦素，一种脂肪组织衍生的激素，传达外周能量储备的状态 对大脑有很强的抑制食欲和增加能量消耗的影响。这些 瘦素的特性最初为肥胖症的治疗带来了极大的兴奋；然而， 肥胖者大脑中的瘦素抵抗阻碍了其作为有效的减肥药物的使用 有治疗作用。我们和其他人之前已经证明，瘦素-内质网(ER)压力增加- 大脑中的反应性神经元在瘦素抵抗的发展中起着核心作用，因此 肥胖症。为了将我们的分子生物学发现转化为治疗，我们使用了系统生物学的方法。 和非传统的硅内药物筛查，以数学算法为动力，针对内质网压力。我们有 发现雷公藤红素和Withaferin A是有效的化学伴侣，可以缓解内质网压力，恢复 胰岛素和瘦素的敏感性，并将肥胖小鼠的体重降低到瘦身水平。雷公藤红素对血管紧张素转换酶的影响 体重(减少约45%-50%)比减肥手术后的体重要强。 我们随后重点研究了雷公藤红素增加瘦素的分子机制。 敏感度。这些努力揭示了白介素1受体1(IL1R1)是雷公藤红素的中间介质。 作用：我们已经证明IL1R1KO小鼠对雷公藤红素的瘦素增敏和抗 肥胖效应。 我们的建议是基于这些先前的观察结果，并有三个具体目标。目标1和 目的2重点鉴定雷公藤红素抗肥胖和抗肥胖作用的下丘脑神经元群。 糖尿病的影响。此外，这些目标计划确定每个已识别神经元的贡献 人群对雷公藤红素的减肥和抗糖尿病作用的不同方面。Aim3建议 确定雷公藤红素作用的分子机制，并利用最新技术鉴定 雷公藤红素影响的分子网络。这一目标的最终目标是确定 雷公藤红素介导瘦素敏化，从而发挥其抗肥胖和抗糖尿病作用。

Obesity is a major cause for the development of debilitating diseases such as type-2 diabetes, cardiovascular disease, hypertension, renal diseases, non-alcoholic steatohepatitis (NASH), all of which reduce life quality as well as lifespan. Despite enormous efforts to develop anti-obesity medications, the drugs that are currently available have had only marginal effects (in the range of 3–10%) on body weight, and most have been withdrawn from the market owing to their side effects. Therefore, there is an urgent need for safe and effective medical treatments for obesity Leptin, an adipose tissue-derived hormone that communicates the status of peripheral energy reserves to the brain has robust influence on appetite suppression and on increasing energy expenditure. These features of leptin initially created great excitement for the treatment of obesity; however the development of leptin resistance in the brains of obese individuals has prevented its use as an effective anti-obesity therapeutic. We and others have previously shown that increased Endoplasmic Reticulum (ER) stress in leptin- responsive neurons in the brain plays a central role in the development of leptin resistance, and consequently of obesity. To translate our molecular biology discoveries into treatment, we used systems biology approaches and unconventional in-silico drug screens powered with mathematical algorithms, to target ER stress. We have discovered Celastrol and Withaferin A as powerful chemical chaperones that alleviate ER stress, restore insulin and leptin sensitivity, and reduce the bodyweight of obese mice to lean levels. The effect of Celastrol on bodyweight (~45-50% reduction) is stronger than that which follows bariatric surgery. We have subsequently focused on the molecular mechanisms of action of Celastrol in increasing leptin sensitivity. These efforts revealed interleukin 1 receptor 1 (IL1R1) as an intermediate mediator of Celastrol's action: we have shown that IL1R1 KO mice are completely resistant to Celastrol's leptin sensitizing and anti- obesity effect. Our proposal is based on these previous observations and has three Specific Aims. Aim 1 and Aim 2 focus on identification of hypothalamic neuron populations that mediate Celastrol's anti-obesity and anti- diabetic effects. Furthermore, these aims plan to determine the contribution of each identified neuron population to the different aspects of Celastrol's anti-obesity and anti-diabetic effects. Aim3 proposes to determine the molecular mechanisms of Celastrol action and utilizes state-of-art techniques to identify molecular networks affected by Celastrol. The ultimate goal of this aim is to determine the exact target of Celastrol in mediating leptin sensitization and consequently its anti-obesity and anti-diabetic effects.