May 23, 2002 SEATTLE -- Thousands of obese Americans know firsthand that gastric bypass surgery can achieve long-term weight loss when dieting, exercise and medications have failed. The reason for the difference may hinge on a recently discovered appetite-stimulating hormone, according to an article in the May 23 New England Journal of Medicine.
A study led by a team at the Veterans Affairs (VA) Puget Sound Health Care System and the University of Washington (UW) compared blood samples from dieters and gastric-bypass patients and found dramatic differences in the levels of "ghrelin," a hormone secreted by the stomach. The hormone was first identified by Japanese researchers in 1999, and was shown by British scientists last year to trigger appetite in humans—the first known hormone to do this.
The new findings may explain why keeping off excess weight through dieting, exercise or even medication is often a constant uphill battle, whereas obese patients who lose up to 200 pounds or more through gastric bypass surgery tend to keep off the pounds permanently. The study shows that dieting raises ghrelin, while gastric bypass surgery sharply reduces it, almost to undetectable levels. The research is the first to document the effects of low-calorie dieting versus gastric bypass surgery on ghrelin levels.
According to lead author David E. Cummings, MD, the findings not only shed light on what may be an underlying reason for the success of gastric bypass surgery, but raise the possibility of a new generation of safer, more effective weight-loss drugs.
"If the absence of ghrelin contributes to the effectiveness of gastric bypass surgery, then we may be able to achieve at least some of that weight loss by antagonizing [blocking] ghrelin medically. If this approach works, then it might be something we could use even for people who are only modestly overweight," said Cummings, an endocrinologist with VA and UW. He added that researchers have yet to develop an antagonist, or molecular blocker, for the hormone.
Currently available weight-loss drugs work mainly by raising levels of the neurotransmitters serotonin and norepinepherine, which can increase metabolism and reduce appetite; or by blocking the absorption of fat in the digestive tract. But many of these medications have potentially serious side effects, such as hypertension. Two drugs—dexfenfluramine and fenfluramine—were pulled from the market in 1997 after being linked to heart damage. Fenfluramine had been used together with phentermine as the popular combination "fen-phen."
Gastric bypass surgery, according to conventional medical wisdom, works because it dramatically reduces the portion of the stomach that is available to accept food. In the operation, 95 percent of the stomach is sewn shut so it can’t receive food. As a result, the patient feels full much sooner and eats less at each meal.
However the new study suggests another mechanism may be at work. Cummings and colleagues believe the cells in the stomach that produce ghrelin become inactive when they are no longer exposed to food in the gut. "We think ghrelin cells ‘go to sleep’ when they’re deprived of contact with ingested nutrients," he said.
To test the theory, the researchers analyzed blood samples from 13 obese patients before and after a six-month low-fat, low-calorie diet, and from five patients who had undergone gastric-bypass surgery within the past one to three years. Ten normal-weight patients served as a control group.
The dieters lost an average of 17 percent of their body weight, and their ghrelin levels rose 24 percent. The surgery group had lost an average of 36 percent of their weight, and their ghrelin levels remarkably had sunk to 77 percent below normal, and 72 percent below the dieters’ level. The very low levels of the surgery group did not show the pre-meal increases and post-meal decreases that were found in normal adults.
According to Cummings, the rise in ghrelin caused by dieting and several other forms of weight loss is part of the body’s normal adaptive response. When we lose weight, the body senses this as famine, and triggers a survival mechanism to keep our weight constant—the metabolism rate drops, and we feel hungrier, so we’ll eat more. That’s the ostensible reason, notwithstanding the new findings on ghrelin, why most diets fail: Will power can forestall the urge to eat more for only a limited time. Gastric-bypass surgery is the only method known to short-circuit this normal body response, perhaps in part by disabling ghrelin-producing cells.
Cummings now plans to study how gastroplasty, or stomach stapling, affects ghrelin. That procedure has been shown in clinical trials to be less effective than gastric bypass surgery, and its usage has declined as a result. Gastric bypass surgery, though not without risks, is seeing a boom in popularity. It is recommended only for so-called "morbidly obese" patients—those with a body mass index of 40 or more, or 35 or more with known medical problems due to obesity.
"It’s reasonable to wonder if the difference in efficacy between the two procedures arises because one shuts off ghrelin and the other doesn’t," said Cummings.
The research was funded by VA and the National Institutes of Health, with additional grants from the Burroughs Wellcome Fund and the Andrew W. Mellon Foundation. Co-authors on the study included David S. Weigle, MD, of UW and Harborview Medical Center in Seattle; R. Scott Frayo, of VA and UW; Patricia A. Breen, of UW and Harborview; Marina K. Ma, of VA and UW; E. Patchen Dellinger, MD, of UW and University Hospital in Seattle; and Jonathan Q. Purnell, MD, of Oregon Health and Science University.
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