Department of Medical and Clinical genetics, Göteborg University, Göteborg, Sweden.
Int J Obes (Lond). 2010 Oct;34 Suppl 1:S43-6. doi: 10.1038/ijo.2010.183.
Obesity is endemic in many regions of the world and a forerunner of several serious and sometimes fatal diseases such as ischemic heart disease, stroke, kidney failure and neoplasia. Although we know its origin--it results when energy intake exceeds energy expenditure--at present, the only proven therapy is bariatric surgery. This is a major abdominal procedure that, for reasons that are largely unknown (it cannot be explained solely by a reduction in ventricular volume), significantly reduces energy intake, but because of cost and limited availability, it will most likely be reserved for only a small fraction of those who stand to gain from effective antiobesity treatment. Clearly, alternative ways to treat obesity are needed. Another way to combat excessive accumulation of white adipose tissue would be to increase energy expenditure. Rodents, hibernators and human infants all have a specialized tissue--brown adipose tissue (BAT)--with the unique capacity to regulate energy expenditure by a process called adaptive thermogenesis. This process depends on the expression of uncoupling protein-1 (UCP1), which is a unique marker for BAT. UCP1 is an inner mitochondrial membrane protein that short circuits the mitochondrial proton gradient, so that oxygen consumption is no longer coupled to adenosine triphosphate synthesis. As a consequence, heat is generated. Mice lacking ucp-1 are severely compromised in their ability to maintain normal body temperature when acutely exposed to cold and they are also prone to become obese. We have shown that, in mice, BAT protects against diet-induced obesity, insulin resistance and type 2 diabetes. This is based on prevention of excessive accumulation of triglyceride in non-adipose tissues such as muscle and liver. Ectopic triglyceride storage at these locations is associated with initiation of insulin resistance and, ultimately, development of type 2 diabetes.
肥胖是世界上许多地区的普遍现象，也是许多严重甚至致命疾病的先兆，如缺血性心脏病、中风、肾衰竭和肿瘤。虽然我们知道它的起源——当能量摄入超过能量消耗时，就会导致肥胖，但目前唯一被证实的治疗方法是减肥手术。这是一种主要的腹部手术，由于我们尚不清楚其原因（仅通过心室容积减少无法解释），它可以显著减少能量摄入，但由于成本和供应有限，它可能仅适用于那些从有效的减肥治疗中获益的一小部分人。显然，需要寻找其他治疗肥胖的方法。另一种对抗白色脂肪组织过度堆积的方法是增加能量消耗。啮齿动物、冬眠动物和人类婴儿都有一种特殊的组织——棕色脂肪组织（BAT），它具有通过一种称为适应性生热的过程来调节能量消耗的独特能力。这个过程依赖于解偶联蛋白 1（UCP1）的表达，它是 BAT 的独特标志物。UCP1 是一种线粒体内膜蛋白，它使质子梯度短路，从而使耗氧量不再与三磷酸腺苷合成偶联。因此，会产生热量。缺乏 ucp-1 的小鼠在急性暴露于寒冷时，维持正常体温的能力严重受损，而且它们也容易肥胖。我们已经表明，在小鼠中，BAT 可以预防饮食诱导的肥胖、胰岛素抵抗和 2 型糖尿病。这是基于防止甘油三酯在非脂肪组织（如肌肉和肝脏）中过度积累。这些部位的异位甘油三酯储存与胰岛素抵抗的发生有关，最终导致 2 型糖尿病的发展。
