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Hungry? Blame a Hormone


The appetite-driving hormone ghrelin, which sounds a bit like the word "gremlin," may well be the dietary devil responsible for those late-night refrigerator raids and the irresistible pull of the office snack cart.

The word entered the popular diet vocabulary two weeks ago when a study about it was published in the New England Journal of Medicine.

Research had shown not only that obese people who dieted had more of the hormone in their blood (and subsequently regained weight) but also that people who underwent gastric bypass surgery made barely any ghrelin--and kept the pounds off.

With the study receiving a blitz of attention, it's easy to jump to the conclusion that if researchers could overpower or neutralize ghrelin, they could achieve the Holy Grail of lasting weight loss.

But such findings demand cool heads, weight loss experts say. Every few years, we learn about another potential miracle discovery--some other chemical that our bodies make that might be harnessed to reverse weight gain.

"These reports seem to come like meteorites: They crash through the sky, and nothing comes in the short term. People come to lose faith and lose confidence," said Dr. Rudolph L. Leibel, a Columbia University weight loss researcher. "People are desperate to find some treatment. There are very few things that attract as much attention as this: sex, body weight and fast cars."

Leibel should know. Back in 1994, he headed one of the two Rockefeller University laboratories that jointly cloned the gene for leptin, a hormone manufactured mostly in the fat cells that tells the brain it's time to go easy on the eating. It was the first hormone found to regulate weight and appetite, and its discovery was a watershed in obesity research, pushing researchers into nearly a decade of what Leibel called "enormous advance and insights into the regulation of body weight."

Although hearts leaped at the early prospects of leptin, neither it nor any of the other brain chemicals found to stimulate or suppress appetite have yet led to good, long-term weight control.

But ghrelin looks different to many researchers, in part because it originates outside the brain, in the digestive system.

Ghrelin is a chemical secreted by cells in the stomach and upper part of the intestine, sending messages about food through the bloodstream to the brain. Levels go up before a meal, telling you it's time to chow down; they drop afterward, telling you it's time to push back from the table.

It seems to provide more biochemical evidence for why dieting becomes such a Sisyphean struggle. In the recent study, obese people who dropped excess pounds had more ghrelin in their blood than they had before dieting, dooming them to regain what they'd lost. (No wonder that the weight we "lose" we tend to "find" again. Our bodies are programmed to lard up against winter starvation. Trouble is, in modern times, we're plagued by the opposite problem, obesity).

Ghrelin is a diet demon in another way too, said Dr. David E. Cummings, lead author of the study published May 23. Not only does the hormone increase appetite and eating, it decreases metabolism and the breakdown of fat.

Cummings, an endocrinologist at the Veterans Affairs Puget Health Care System and the University of Washington, found that obese people who underwent gastric bypass surgery had very little ghrelin in their bloodstreams. Doctors had suspected these folks' ability to keep off 100 or more pounds stemmed from more than having their stomach capacity reduced by 95% and their food rerouted so their intestines absorbed fewer nutrients.

Cummings' research suggests that the stomach's ghrelin-producing cells somehow turn off after the surgery, cutting off the hunger signal to a section of the hypothalamus in the brain called the arcuate nucleus. Therefore, a logical strategy would be to find ways to suppress ghrelin so that overweight patients could lose while avoiding the risks of surgery.

Obesity has surged to the top of the nation's public health agenda, especially because it's a potent driver of diabetes, heart disease and cancer. The pharmaceutical industry has spent billions of dollars trying to deliver permanent weight loss in a pill: metabolism speeder-uppers such as amphetamines, fat-blockers such as orlistat (Xenical), appetite suppressants such as phentermine (half of the banned fen-phen combination) and sibutramine (Meridia), which was just in the news in May when a consumer group accused the manufacturer of withholding information in at least seven users' deaths. Cummings called ghrelin "an appealing target" for drug makers, several of which had ghrelin studies under way before his results came out. "It also doesn't take a lot of thought to realize a cure for obesity would be the biggest cash cow any drug company has ever seen," he said.

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