Adipose CaMKI: a pivotal controller of triglyceride metabolism

在英国，肥胖是一个重要且日益严重的公共卫生问题。虽然超重本身通常不是不健康的，但肥胖会使人容易患上其他更严重的健康问题。由肥胖引起的最常见的疾病之一是2型糖尿病，在这种疾病中，身体不再对胰岛素做出适当的反应。肥胖本身的许多方面，以及它可能导致的疾病，都没有得到很好的理解：我们不完全了解身体的其他部位是如何与脂肪细胞沟通的，我们也不完全了解脂肪细胞如何相互沟通，以调节它们所含的脂肪量；我们并不完全了解这些细胞之间的交流是如何导致脂肪堆积的变化的。这些细胞问题的答案将帮助我们理解为什么有些人会肥胖而有些人不会，为什么有些肥胖者会患糖尿病而有些人不会。我们将在果蝇中研究这些问题。苍蝇和人的许多代谢调节机制是相似的，但是用苍蝇来研究相对容易和便宜。我们意外地发现，一种叫做CaMKI的基因是果蝇正常脂肪代谢所必需的。没有CaMKI基因的果蝇非常肥胖——它们的脂肪是正常果蝇的四倍——但它们也很健康：它们和正常果蝇一样长寿，而且显然没有糖尿病。这表明CaMKI在控制脂肪积累和糖尿病的发展中很重要。CaMKI是一种叫做激酶的蛋白质。激酶通过修饰其他蛋白质发挥作用；激酶活性通常对来自细胞外的信号作出反应。我们的实验将测试CaMKI如何参与脂肪细胞接收其他组织信号的能力，CaMKI是否参与糖尿病的发展，以及CaMKI实际上如何改变脂肪的积累——哪些蛋白质被CaMKI修饰，这种修饰的效果是什么。我们的初步结果，结合我们提出的实验，代表了我们对脂肪细胞如何控制其脂肪水平以及脂肪积累如何导致糖尿病的认识迈出了戏剧性的一步。我们的工作将对代谢调节和代谢性疾病产生重大影响，并可能帮助我们理解“健康”肥胖的本质。

Obesity is a significant, and growing, public health issue in the United Kingdom. Though overweight itself is often not unhealthy, obesity can predispose people to develop other, more serious, health problems. One of the most common diseases caused by obesity is type-2 diabetes, in which the body no longer responds properly to insulin. Many aspects of obesity itself, and the diseases it can cause, are not well understood: we don't fully understand how other parts of the body communicate with adipose (fat) cells, and we don't fully understand how adipose cells communicate with one another, to regulate the amount of fat they contain; we don't fully understand how the communications between these cells actually causes changes in fat accumulation. The answers to these cellular questions would help us understand why some people become obese and others don't, and why some obese people develop diabetes and others don't.We will study these issues in fruit flies. Many of the mechanisms of metabolic regulation are similar between flies and people, but flies are relatively easy and inexpensive to work with. We have unexpectedly found that a gene called CaMKI is required for normal fat metabolism in flies. Flies that don't have CaMKI are extremely obese--they have about four times as much fat as normal flies--but they are also healthy: they live as long as normal flies and apparently are not diabetic. This suggests that CaMKI is important in controlling fat accumulation and also in the development of diabetes.CaMKI is a kind of protein called a kinase. Kinases function by modifying other proteins; kinase activity is often responsive to signals from outside the cell. Our experiments will test how CaMKI is involved in the adipose cells' ability to receive signals from other tissues, whether CaMKI is involved in the development of diabetes, and how CaMKI actually works to change the accumulation of fat--what proteins are modified by CaMKI and what the effects are of that modification.Our preliminary results, combined with the experiments we propose, represent a dramatic step in our knowledge of how adipose cells control their fat level and how fat accumulation can lead to diabetes. Our work will have significant implications regarding metabolic regulation and metabolic disease and may help us understand the nature of "healthy" obesity.