Sci. Aging Knowl. Environ., 11 August 2004
Genetic modification that turns fat cells into furnaces extends longevity in mice
Fat cells pack away grease like squirrels hoarding nuts in September, and making the cells less thrifty might help fend off obesity, according to new work in mice. The genetically altered rodents snarfed more food but lived long and remained lean. The results suggest that igniting fat metabolism might extend life span without drastic dieting.
As people gain weight, they need a place to put the excess calories, and fat cells provide such storage. Molecules called CCAAT/enhancer-binding proteins (C/EBPs) help prod fat cells to mature. C/EBPs come in five flavors, including the and forms. Mice lacking C/EBP die before birth, so investigating that protein's function has posed problems. Four years ago, physiologist Ying-Hue Lee of the Academia Sinica in Taiwan and colleagues replaced the form with the one, which researchers know from test tube experiments serves some of the same purposes. The rodents, which carried four copies of the gene, accumulated less fat than did controls. In a new study, the researchers assessed how the modification changed life span and metabolism.
The mice outlier controls by more than 20%. They gobbled extra food but scampered the same amount, indicating that they use the surplus energy in another way. Fat from the altered rodents carried plumper mitochondria, a sign of increased metabolic activity. Moreover, the modified animals pumped out larger quantities of two mitochondrial proteins, suggesting that the organelles were working harder. Mitochondria can transform food energy into ATP--a cell's fuel--or release it as heat. Fat cells from the modified mice made more of the RNA blueprint for an uncoupling protein, which shifts the organelles toward heat production. Together, these findings indicate that the rodents' fat cells were tuned to expend energy.
The team also found that fat cells from the genetically engineered animals manufactured increased amounts of the Gs protein, which helps incite fat breakdown. Altering normal fat cells to make more Gs hiked their oxygen consumption, increased their number of plump mitochondria, and shrank their lipid stockpiles. Control cells, by contrast, bore no hefty mitochondria and amassed fat. Coaxing fat cells to burn rather than stow fat, possibly by rousing Gs, might provide a new strategy for fighting obesity, says Lee.
Researchers now have some explaining to do, says molecular biologist John Papaconstantinou of the University of Texas Medical Branch in Galveston. According to conventional wisdom, he says, cranking up fat metabolism should churn out more ruinous reactive oxygen species (ROS), which might shorten life. The study raises the question of "how this [longevity] mechanism relates to other signaling pathways that affect aging," many of which dampen ROS output. That the rodents ate more but survived longer clashes with evidence that austere diets, known as calorie restriction, prolong life, says molecular nutritionist Jacob Friedman of the University of Colorado Health Sciences Center in Aurora. But the work hints that "there's another way to get longevity other than calorie restriction." Scientists might be able to devise new methods for preventing obesity if they can figure out how to make fat cells less miserly.
August 11, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150