为什么一些人竭力控制饮食依然肥胖？为什么一些人吃得不少照样苗条？答案可能在基因中。美国一个研究小组发现，一种名为CRTC3的基因可以放慢脂肪消耗速度。人体若缺乏这种基因，则脂肪消耗快，不容易发胖。
基因开关
索尔克生物研究所生物学家马克蒙特米尼带领的研究小组发现，普通老鼠和丧失CRTC3基因的老鼠正常进食时，两者体重未发生明显变化。但喂它们吃高热量饮食后，只有正常老鼠发胖。另外，丧失CRTC3基因的老鼠棕色脂肪细胞数量是普通老鼠的两倍。
棕色脂肪细胞燃烧白色脂肪细胞中的脂肪，产生热量，维持动物体温。一些研究显示，身材偏瘦者棕色脂肪细胞含量高于偏胖者。
蒙特米尼告诉每日科学网站：“CRTC3可能是控制棕色脂肪细胞数量的开关，如果能产生更多棕色脂肪细胞，就可能控制肥胖。”
研究人员比较两组墨西哥裔美国人的体重后发现，CRTC3基因活跃的一组偏胖。
研究报告12月16日由英国《自然》杂志刊载。
进化结果
蒙特米尼分析，人类在进化过程中，发展出应对饥饿的机制，即经由CRTC3这类基因的表达，放慢燃烧脂肪的速度。
这种机制对人类祖先意义重大，因为他们往往吃饱一顿要等好长一段时间才能猎取到下顿食物，需要在身体内存贮热量。那些体内“省吃基因”活跃的人具有生存优势，可以长时间不吃东西存活。
对现代人而言，这种机制可能是一种累赘，可能导致脂肪在体内堆积，威胁健康。
科学家上世纪60年代就想到人体内可能存在“省吃基因”，当时对基因的认识远不如现在。
协助治疗
蒙特米尼带领的研究小组希望他们的发现给治疗肥胖症、减少人们患糖尿病等疾病风险开拓一条新路。
基于这项研究，制药企业可以开发药物抑制CRTC3基因的作用。医生可以从一个人体内CRTC3基因活跃程度掌握这个人患肥胖症风险是否偏高，从而采取应对措施。
并非所有体内CRTC3基因活跃的人都趋向发胖，例如，研究人员未发现这种基因与美国白人体重之间存在关联。研究人员认为，生活环境和生活方式同样会影响体重。
蒙特米尼说：“治疗糖尿病或肥胖症的方法应该因人而异。”
每日科学网站的数据显示，7200万美国成年人受肥胖症困扰。
Feast, Famine and the Genetics of Obesity: You Can't Have It Both Ways
That is one conclusion drawn by researchers at the Salk Institute for Biological Studies, who recently showed that mice lacking a gene regulating energy balance are protected from weight gain, even on a high fat diet. These findings have implications for the worldwide obesity epidemic and its consequences, such as type two diabetes.
In the December 16, 2010 issue of Nature, a team led by Marc Montminy, M.D., Ph.D, professor in the Clayton Foundation Laboratories for Peptide Biology, reports that a gene known as CRTC3 decreases energy expenditure by fat cells. "Ideas about obesity are based on concepts of feast or famine," said Montminy. "As humans, we developed ways of coping with famine by expressing genes like CRTC3 to slow the rate of fat burning. Individuals with these active "thrifty genes" had an advantage-they could survive long periods without food."
The idea that mammals harbor genes that slow fat burning was proposed in the 60's, before any genome was sequenced. Some theorized that such thrifty genes provided a survival advantage to our hunter-gatherer ancestors, who often went a long time between meals and needed to hold on to their fat depots. In 2010, however, those genes have become a liability.
To analyze its role in fat metabolism, the researchers engineered mice lacking the CRTC3 gene and put them on diets of varying fat composition. Normal and CRTC3 gene "knockout" mice appeared similar when fed a moderate fat diet. But when fed the mouse version of the Philly cheese steak diet, only the normal mice became obese. "The CRTC3 knockout mice were leaner and protected from obesity," reports Montminy. "They also had about twice as many brown fat cells than did normal mice."
To appreciate this finding, keep in mind that not all fat cells are "bad." When you deplore your waistline, what you are deploring is white fat tissue (also called WAT, for "white adipose tissue"), which serves as a fat storage depot around the midsection and hips. However, a second type of fat-known as brown fat (BAT)-is downright desirable.
"Brown fat is very different from white fat," says Youngsup Song, Ph.D., a postdoctoral fellow in the Montminy lab and the study's first author. "Brown fat tissue burns fat that has accumulated in white fat tissue to generate heat as a way to maintain body temperature."
In fact, some evidence suggests that humans with a genetic propensity to leanness have more brown fat cells than do "ample" individuals. As desirable as that trait may seem in a "super-size me" world, those folks likely had a pretty tough time in the Paleolithic era.
Although the researchers found that CRTC3 loss also perturbs how all fat cells respond to brain signals controlling energy expenditure, they remain particularly intrigued by the brown fat connection. "CRTC3 could be a switch controlling the number of brown fat cells, " says Montminy. "That is key, because if you could make more brown adipocytes, you could potentially control obesity."
To explore how relevant these studies are to humans, Montminy asked clinicians at Cedars-Sinai Medical Center in Los Angeles to search databases of patient genetic information for a particularly interesting human CRTC3 gene mutation, which appeared to represent a more potent form of the normal gene.
Since mice lacking CRTC3 resist obesity, the researchers reasoned that people carrying a revved-up version of the gene might show the opposite tendency. Indeed genetic testing of two groups of Mexican American patients revealed that individuals harboring the active CRTC3 mutation showed increased incidence of obesity.
"This is an example in which findings from rodent research led to a novel discovery in humans," says Mark Goodarzi, M.D., Ph.D., an endocrinologist at Cedars-Sinai and collaborator in the study. "Not all Mexican American individuals with the variant will develop obesity, but those carrying it are at higher risk." Interestingly, non-Hispanic Caucasians carrying the variant do not show increased obesity, a difference likely related to environmental or lifestyle factors.
Overall this study illustrates an important principle: that what is genetically advantageous in one cultural or historic context may not be in another. In fact, Montminy does not view obesity as an aberration or a "disease." "Storing fat in adipose tissue is a normal response. A lot people are obese but do not develop type 2 diabetes," he says, suggesting that genes like CRTC3 could serve as diagnostic tools as well as drug targets. "A goal is to go to your doc and learn whether you have the risk factors to progress to diabetes."
Also contributing to the study were Judith Altarejos, Ph.D., Hiroshi Inoue, MD, Ph.D., Rebecca Berdeaux, Ph.D., Jeong-Ho Kim, Ph.D., Jason Goode, Motoyuki Igata, MD., Jose Paz, Ph.D., Meghan Hogan, Pankaj Singh, Ph.D., Naomi Goebel, Lili Vera, and Nina Miller-all of the Salk Institute-and Xiuqing Guo, Michelle Jones, Yii-Der Chen, Kent Taylor, and Jerome Rotter, MD, of Cedars-Sinai Medical Center in Los Angeles, and Willa Hsueh, MD, of Methodist Hospital Research Institute in Houston.
The research was funded by grants from the National Institutes of Health, the Kieckhefer Foundation, the Clayton Foundation for Medical Research, the Helmsley Foundation, the Cedars-Sinai Winnick Clinical Scholars Award, and the Cedars-Sinai Board of Governors Chair in Medical Genetics.
