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Body's 'Fat Hormone' Gives Up More Secrets

High blood fat may prevent leptin from telling brain to curb appetite in obese

MONDAY, April 26, 2004 (HealthDayNews) -- It's supposed to tell the brain to stop eating when body fat levels get too high, but for some reason the hormone leptin fails those people who need it the most, the overweight and obese.

Now scientists believe they've found out why.

The discovery could someday lead to safe, effective treatments in the war against widening waistlines, the researchers say.

"We're very, very excited," said study author Dr. William A. Banks, a physician at the VA Medical Center in St. Louis. "In the pre-leptin days, which were not that long ago, we had to tell our obese patients, 'No, you don't have a hormonal problem, you just eat too much.'"

"Our thinking has now changed 180 degrees to where we realize that, no, obesity has some underlying endocrine problems -- and if we figure those out, we can treat it," he said.

The study appears in the May issue of Diabetes.

The discovery a decade ago of leptin, a natural appetite-suppressing hormone secreted by fat cells, has been hailed in recent years as a breakthrough in obesity research.

"It's a peptide or protein that's produced by fat, goes to the brain, and makes the brain make you eat less," Banks explained. "It also increases your body temperature slightly, so you burn calories a little faster."

Eat less, burn more calories: In a perfect world, leptin should be the perfect weight-control agent. But scientists quickly discovered the "leptin paradox" -- as body fat rises and leptin output increases, leptin's appetite-suppressing effect on the brain actually declines.

It's been "a puzzle," said leptin expert Dr. Roger H. Unger, chairman of the University of Texas Southwestern's Touchstone Center for Diabetes Research in Dallas. "People have wondered why, if leptin keeps going up as you get fatter and fatter, you don't see its [appetite-suppressing] effects, which you do see when you give leptin to a normal-weight person."

Banks and his team suspected the problem could lie in leptin being denied full access to the brain. "Because it's so special, the brain, unlike other tissues, is protected by the blood-brain barrier," he explained. This means all blood vessels within the brain are specially sealed to prevent the infiltration of chemicals and pathogens that could cause it harm.

"Leptin is a large molecule," Banks said, "so the only way it can get from the blood into the brain is being transported across the barrier by its own transport system." In the obese, something appears to stop leptin from jumping this barrier.

That something may be high levels of blood fats called triglycerides, the researchers report. In experiments conducted with mice, the St. Louis team discovered a rise in triglyceride levels appears to prevent leptin from crossing the brain's protective barrier.

Triglycerides are unhealthy fats that come from many types of food. While leptin functioned normally in mice fed triglyceride-free skim milk, the hormone had little or no effect in curbing the appetites of mice fed whole milk loaded with triglycerides, the researchers report.

The take-home message for humans is clear, according to Banks: "If you're unfortunate enough to be one of those people who ups their triglycerides when they are obese, you're going to have more trouble getting leptin into the brain, so the brain isn't going to see the leptin." The result, he said, is that appetite centers in the brain continue to crave high-calorie meals -- even as the overweight pack on the pounds.

Banks cautioned that although mice do present "a very nice model" for human weight gain, much more research into leptin and triglycerides remains before any solid recommendations can be made.

"There are drugs that will lower triglycerides," he said, "but it would be inappropriate to suggest that people try these drugs on their own or even ask their physician for them. We still need to do more studies to test this out in a controlled, safe way. And triglyceride-lowering drugs are not without side effects."

However, healthy eating and regular exercise remains a safe, effective method of lowering triglyceride levels in the blood. "People, if they diet and exercise, can fight this," he said. "You don't have to wait on the science -- we can all be exercising more and eating more sensibly."

Unger called the finding "a step forward" in obesity research. But he's disappointed the researchers didn't go further, comparing the eating patterns of high-triglyceride and low-triglyceride mice over time.

"This study shows that leptin's access to the brain is going to be reduced if the levels of fat [in blood] are high. What the researchers didn't do, though, is see if that's going to change food intake," he said.

The St. Louis researchers said they plan more studies into the relationship between triglyceride-lowering diets and medications and their effect on leptin-induced appetite control.

"We can help leptin be more effective," Banks said. "Leptin isn't the bad guy; leptin is struggling like all of us, against our lifestyles."

More information

Get an overview of obesity and overweight from the U.S. Centers for Disease Control and Prevention. Find a review of leptin and other molecules involved in obesity at Duke University.

SOURCES: William A. Banks, M.D., physician, VA Medical Center, and professor, geriatric medicine, St. Louis University, St. Louis; Roger H. Unger, M.D., chairman, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas; May 2004 Diabetes
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