Lipotoxicity, the link between obesity and the Metabolic Syndrome: pathogenic mechanisms and therapeutic strategies.

肥胖和肥胖相关的糖尿病正变得越来越普遍。这些天来，我们看到越来越多的肥胖儿童患上了以前只在成年人中看到的同一类型的糖尿病。随着过早肥胖人口的老龄化，与肥胖和糖尿病相关的并发症出现得越来越频繁。肥胖和糖尿病患者早年死亡的风险很高，主要死于心脏病发作。理想的策略是防止人们变得肥胖，但很明显，通过公共卫生措施或药物治疗来预防肥胖正在失败。我们的最终目标是防止肥胖者患糖尿病和心脏病发作。为了做到这一点，我们调查肥胖是如何导致糖尿病或心脏病的，以及如何在肥胖状态下处理或预防这些疾病。我们认为，主要问题是肥胖者未能将脂肪储存在正确的位置，即脂肪组织。当脂肪组织变得饱满时，脂肪就会溢出到其他器官，如肝脏。当脂肪在肌肉或肝脏等器官中积聚时，就会产生毒性效应，这一过程我们称之为脂毒性。在这项拨款申请中，我们研究了脂肪的这些毒性效应是如何发生的，以及我们可以做些什么来治疗或预防它。为此，我们需要使用老鼠模型，以充分了解全身是如何处理多余脂肪的。我们提出的策略包括：a)使脂肪组织更健康，以便更好地捕捉脂肪；b)增加器官(如肌肉，甚至脂肪组织本身)燃烧脂肪的能力。虽然这可能不能治愈肥胖，但至少可以防止人们死于肥胖症。我们希望我们的研究将有助于控制即将到来的由肥胖引起的心脏病发作、糖尿病和中风的流行。

Obesity and obesity-associated diabetes are becoming more and more common. These days we see more obese children developing the same type of diabetes that previously was seen exclusively seen in adults. Complications related to obesity and diabetes are presenting more frequently as this prematurely obese population ages. Obese and diabetic individuals are at high risk of dying at an early age, principally from heart attacks. The ideal strategy would be to prevent people becoming obese, but it is clear that obesity prevention, be it by public health measures or drug treatments, is failing. Our final goal is to prevent obese people from becoming diabetic and having heart attacks. To do this we investigate how being obese causes diabetes or heart disease and how to tackle or prevent these diseases in an obese state. We think that the main problem is that obese people fail to store fat in the correct place, which is adipose tissue. When adipose tissue becomes full then fat spills over into other organs such as the liver. When fat accumulates in organs such as muscle or liver it has toxic effects, a process we call lipotoxicity. In this grant application we study how these toxic effects of fat occur, and what can we do to treat it or prevent it. For this we need to use mouse models, to fully understand how the whole body deals with excess fat. The strategies we propose include; a) to make the adipose tissue healthier so it can trap fat better, b) increasing the capability of organs (such as muscle and even adipose tissue itself) to burn fat. While this may not cure obesity it may at least prevent people from dying from it. We hope our research will help to control the coming epidemics of heart attacks, diabetes and strokes caused by obesity.