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Studies find a way our bodies may fight obesity

Studies find a way our bodies may fight obesity

By David Brown
Washington Post
Posted: 04/08/2009 06:32:26 PM PDT

WASHINGTON — Three new studies show that most adults have unexpectedly large and active deposits of a calorie-burning kind of fat that biologists once thought disappeared after infancy.

The persistence of brown fat suggests a potential new strategy to fight obesity, which is epidemic in the United States and increasing rapidly in the developing world. In addition to eating less and exercising more, people may one day be able to stimulate their bodies to get rid of stored energy — in the form of ordinary fat — purely as heat.

"It is, in a sense, the discovery of a new organ," said Sven Enerback, a researcher at the University of Goteborg in Sweden and the lead author of one of three studies appearing today in the New England Journal of Medicine.

"This is a tissue whose sole physiological purpose is to expend energy," said Francesco Celi, a metabolism researcher at the National Institutes of Health, whose commentary accompanies the studies. "That makes it an ideal target" for drugs or other measures designed to make it more active.

At the moment, however, the only safe way of activating brown fat is to stay chilly, right at the verge of shivering, for prolonged periods. That reproduces the conditions that led to the evolution of brown fat — namely, life-threatening cold in babies and small furry animals that can't put on clothes to keep themselves warm.

Although the new research poses a difficult question — Which would you rather be, thin or warm? — the ultimate goal is to find a less uncomfortable way exploit this ancient adaptation.

The three studies add to the emerging view that brown fat is involved in the body's complicated energy balance and may play a role in diseases such as Type 2 diabetes that can arise when that balance is thrown off.

For example, leaner people have more detectable brown fat than overweight people. Brown fat also appears to be more active in women than men, even though obesity is more prevalent in women. Studies show that stimulating the production of brown fat in mice — a species in which it is naturally plentiful — makes them resistant to gaining weight or to developing diabetes when fed a high-calorie diet.

In human beings, it is unclear whether brown fat is more a cause of leanness or a result of it.

Virtually all cells have microscopic "power plants" called mitochondria, where energy sources such as sugars and fats are burned to produce a compound called ATP, the universal "coin" of the body's economy. Brown fat cells are loaded with mitochondria, but in them the various enzymes that lead to the production of ATP are "uncoupled" from each other. The result is that the energy in the glucose and fat is lost as heat, the way the work of a car engine is lost as heat if the car is stuck in a snowbank with its tires spinning.

In one of the new studies, researchers at Maastricht University Medical Center, in the Netherlands, examined 24 young men, about half of them lean and half overweight. Each was kept in a cool room (61 degrees Fahrenheit) for two hours and then give a PET scan, which lights up any tissue that is using a lot of glucose, showing that it is highly active on a metabolic level.

After the men had been kept cold, activated brown fat deposits were seen in 23 of 24 of them. (The one in which there was no activation was the heaviest). Lean men had about four times the brown fat activity as the overweight men. When several were retested without first being cold, there was no brown fat activity.

In a second study, the Swedish team led by Enerback kept five volunteers in a cool room for two hours and then PET-scanned them while intermittently putting one foot of each subject in an ice-water bath. Brown fat deposits lighted up each time. In three, the tissue was then biopsied and proved to be brown fat.

In the third study, Ronald Kahn and Aaron Cypess, of the Joslin Diabetes Center in Boston, examined PET scans performed on 1,972 patients for various reasons over a three-year period. What appeared to be active brown fat was visible in 7.5 percent of the women and 3.1 percent of the men.
That was a much lower prevalence of detectable brown fat found in either of the other two studies. There are a number of possible reasons.

The Boston researchers did not attempt to induce activity in the brown fat by cold exposure (although PET scans done on days it was cold outside were more likely to light up). The patients also included many elderly, overweight and diabetic patients — all conditions in which brown fat activity is less likely.

Other studies and extrapolation from animal experiments suggest that brown fat could be responsible for as much as one-fifth of the energy we burn at rest. Fully stimulated, the tissue might be able to burn off 10 pounds in a year.

Research published over the summer by Kahn and his colleague at the Joslin Center, Yu-Hua Tseng, showed that when mice are injected with a growth factor called BMP7, they grow more brown fat. Kahn said he thinks ways will be found to increase brown fat in human beings "a lot, at least in activity if not in amount."

Enerback, the Swedish scientist, agreed that the search for a drug that stimulates brown fat "is definitely something we should pursue." He added, however, that "I don't think there will ever be a pill that substitutes for a fundamental change in lifestyle in the treatment of obesity."


研究显示: 人体有自身抗御肥胖的机制

华盛顿——三项新研究显示大多数成年人具有可燃烧卡路里的脂肪沉积物,一种生物学家曾认为婴儿期后消失的脂肪。

棕色脂肪的存留提示了一种新的有潜力的控制肥胖症的策略,肥胖症在美国很流行,且在发展中国家正迅速增加。除了少吃多运动外,也许有一天人们能够刺激他们的机体摆脱贮存的能量——普通型式的脂肪——纯粹的热量。

“从某种意义上说,这是一个新机制的发现。”瑞典哥德堡大学的研究人员Sven Enerback说,他也是今天出现在《新英格兰医学》杂志上三项研究其中之一的第一作者。

“这种组织唯一的生理目的是消耗能量。”国立卫生研究院研究新陈代谢的Francesco Celi说,他的评论紧随那些研究之后。那是旨在使其更活跃的药物或其他措施的理想靶点。

然而,目前,激活棕色脂肪的唯一安全方式是保持寒冷,即长期处于颤抖的状态。那是产生棕色脂肪的条件——换句话说,寒冷可以威胁婴儿和小皮毛动物的生命,因为他们还不能穿衣来御寒。

虽然新研究带来一个难题——你是要瘦还是要温暖?——最终的目标是要找到一种利用这种适应能力的较为舒服的方式。

这三项研究增添了新观点,即棕色脂肪参与机体复杂的能量平衡并可能在2型糖尿病(能量平衡打破后可发生2型糖尿病)中发挥着重要的作用。

例如,瘦人与超重者相比有更多可检测的棕色脂肪。棕色脂肪在女性中比在男性中更活跃,即使肥胖症在女性中更流行。研究显示刺激小鼠棕色脂肪的产生——天生棕色脂肪丰富的物种——能够使其抵御高脂饮食诱导的肥胖和糖尿病。

在人类中,还不清楚棕色脂肪是瘦弱的原因还是其结果。

事实上所有的细胞在显微镜下观察都有被称为线粒体的“发电厂”,在线粒体里,糖和脂肪等能量来源燃烧产生称为ATP(三磷酸腺苷)的复合物,即机体这一经济中的通用“货币”。棕色脂肪细胞里装载着线粒体,但它们中产生ATP的各种酶彼此互不耦联。其结果是葡萄糖和脂肪中的能量以热能的形式丢失,就像是汽车陷入雪堆里轮胎打滑时发动机的热损失。

其中一项新研究中,荷兰马斯特里赫特大学医学中心的研究人员,检测了24名青年男性,他们中一半偏瘦一半超重。每个人都在一间冷室里(华氏61度)呆两小时,然后进行PET扫描,它可以照亮任何正在使用葡萄糖的组织,提示高活力的新陈代谢水平。

那些男性接受寒冷后,24人中有23人检测到激活的棕色脂肪沉积物。

第二项研究中,Enerback领导的瑞典小组让5名志愿者在冷室中呆了2小时,然后进行PET扫描,期间间歇地让每个受试者的一只脚进行冰水浴。棕色脂肪沉积物每次都被照亮。第三步,把那些组织做活检,证实是棕色脂肪。

第三项研究中,波士顿乔斯林糖尿病中心的Ronald Kahn 和 Aaron Cypess,在超过3年的时间中对1972名患者进行了PET扫描。有活性的棕色脂肪在女性中为7.5%,而在男性中为3.1%。这远远低于其他两项研究中任何一项里发现的可探测的棕色脂肪。那有很多可能的原因。

波士顿的研究人员并没有试图通过寒冷暴露来诱导棕色脂肪的活性(尽管PET扫描在寒冷天气里做会更加明亮)。患者也包括很多老年人,超重者和糖尿病患者——所有棕色脂肪活性低的条件。

其他研究和来自动物实验的推论表明棕色脂肪消耗了我们休息时燃烧的能量的五分之一。充分刺激的话,该组织可能一年可以燃烧10磅。

由Kahn和他在乔斯林中心的同事曾玉华(音译)去年夏天发表的研究,显示给小鼠注射名为BMP7的生长因子时,它们产生更多的棕色脂肪。Kahn教授说他认为将来即使不能增加棕色脂肪细胞的数量,也一定能够发现发现大大提高其活性的方法。

瑞典科学家Enerback认为寻求刺激棕色脂肪的药物“无疑是我们应该追求的东西”。然而,他补充说“我不认为一个药丸可以替代肥胖症治疗中需要根本生活方式的转变。”


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