Mice missing protein burn more fat

PHILADELPHIA — Scientists are learning how they might stoke the body’s fat-burning furnace by turning up a molecular thermostat.

Mice lacking a protein that responds to the hunger-promoting hormone ghrelin burn more energy in their brown fat than other mice, Yuxiang Sun of Baylor College of Medicine in Houston reported December 13 at the American Society for Cell Biology’s annual meeting. This revved-up brown fat helps keep mice lean and energetic into middle age. The finding could eventually lead to a way to help people fight obesity.

Brown fat burns energy instead of just storing it the way white fat does. This metabolically active fat is important in helping rodents and other animals maintain their body temperature. Recently researchers learned that adult humans have brown fat, and that the amount of energy burned by brown fat decreases with age and weight. The discovery has spurred interest in learning how to turn brown fat on.

Sun and her colleagues didn’t start out trying to rev up brown fat. Because the hormone ghrelin has been shown to make animals eat more, the researchers reasoned that blocking the molecule’s activity might reduce appetite and help animals and people lose weight. Sun and her colleagues genetically engineered mice to completely lack either ghrelin or the ghrelin receptor, a protein that interacts with ghrelin and sets off a series of biological reactions in cells that leads to the hormone’s effect.

Disappointingly, mice lacking either molecule ate and exercised just as much as normal mice. But mice lacking the ghrelin receptor burned more energy and stayed lean even as they aged, while normal mice and mice lacking ghrelin tended to gain weight as they got older.

Mice missing ghrelin had a hard time maintaining their body temperature when placed in the cold. But mice without the ghrelin receptor stayed warm. Those pieces of evidence led Sun and her colleagues to examine brown fat in the mutant mice.

Sun’s team found that removing the ghrelin receptor causes brown fat cells to make more of a protein called UCP1. That protein makes the cell’s power plants less efficient and as a result, they release more heat. These inefficient brown fat cells may burn their own supply of fat and then gobble up fat that otherwise would be stored in white fat cells, leading to leaner rodents, Sun speculated.

If researchers can discover why removing the ghrelin receptor turns up brown fat’s furnace, it may be possible to design a drug that will do the same thing. “There may be more than just exercise and willpower that can keep us in shape,” Sun said.

There is no question that increasing the activity of brown fat can have a big effect on weight, said Lewis Landsberg, an endocrinologist at Northwestern University in Evanston, Ill. About 10 percent of a rodent’s total energy expenditure comes from brown fat. Extrapolating to humans, turning up brown fat to burn a similar amount of a person’s calories would be about equal to the energy burned while walking 2.5 miles each day, he said.

Landsberg said that it is not clear whether removing the ghrelin receptor directly affects the energy expenditure of brown fat or if the mutation somehow spurs the sympathetic nervous system to turn up the furnace.

Sun hopes to answer that question by removing the ghrelin receptor in just brown fat cells.


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