Nervy approach to fighting fat
Weight loss surgery works, but is so invasive and has such unpleasant long-term side effects that it’s recommended for only a fraction of the obese population, and even many in that group are reluctant to undergo the surgery. In hunting for a simpler and safer alternative, researchers have zeroed in on a nerve that carries much of the communication between brain and gut.
Disrupting this communication, they believe, could lead to safe, effective and sustained weight loss -- mainly by cutting off signals from the gut that tell the brain it’s time to eat. The concept still has to be validated, says Dr. Philip Schauer, immediate past president of the American Society for Metabolic and Bariatric Surgery, a Gainesville, Fla.-based association of U.S. weight loss surgeons, “But if it gives even a modest amount of weight loss, it could be a winner.”
Two different methods of disrupting the vagus nerve are now in clinical trials. One method, vagotomy, simply cuts the nerve and permanently disables it. The other, vagal nerve blocking, uses an electric current to periodically confuse the nerve and prevent it from transmitting signals. Preliminary results suggest that both methods help to safely reduce excess body weight by about 20% on average within six months of therapy.
Amid the complex set of muscles, nerves and organs that team up to regulate body weight, one anatomical feature stands out: the vagus nerve. Running from the brain through the esophagus and branching out to reach nearly every part of the digestive system, this nerve plays a key role in weight gain.
When the stomach is empty, the vagus nerve informs the brain and triggers the feeling of hunger. When the stomach contains food, the vagus tells the brain and relays back the brain’s commands to secrete stomach acid to help digest the food. The brain’s control of the passage of food through the digestive system also relies on the vagus nerve. In short, without the vagus, we would get less hungry, and food would stay longer in the stomach.
The vagus nerve does even more than that. While food is being digested, the brain tells the pancreas to make insulin, a hormone that helps store energy from food in fat tissues. That command passes through the vagus nerve. So too does another that instructs fat tissues to grow by absorbing more nutrients. “Everything this nerve does is designed to make you take up energy and put it into your fat,” says Dr. Robert Lustig, a pediatric endocrinologist at UC San Francisco and one of the lead investigators in a 30-patient clinical trial of vagotomy for weight loss. “It’s your energy storage nerve.”
First noticed in the 1940s
The vagus nerve’s pivotal role in weight gain would appear to make it a prime target of obesity therapy. But this potential was discovered almost by accident in the 1940s, when surgeons treating intractable ulcers tried vagotomy to help reduce stomach acidity. The method worked, and soon became widely used (drug therapy eventually superseded it). But the operation had an unexpected side effect: It made obese patients lose weight.
Early vagotomy surgeries cut the entire vagus nerve as well as some stomach muscles. This drastic method caused undigested food to be dumped into the intestines, leading to a range of unpleasant side effects, such as diarrhea, vomiting, flushing and dizziness.
The modern form of the procedure is much more refined: It cuts only the parts of the vagus that control hunger and weight gain, leaving the stomach muscles and the rest of the nerve intact. As a result, the side effects of vagotomy are now much milder and tend to disappear after a few months, Lustig says.
Launched in 2005, the trial Lustig is involved in is taking place at UC San Francisco and the University of Rochester. About 80% of the 30 subjects in the trial lost an average of about 30% of their excess body weight in the first six months, Lustig says. The trial is sponsored by EndoVx, a Napa-based company that is developing a device to simplify the vagotomy procedure.
One of Lustig’s patients, 57-year-old Garth Michaels of Walnut Creek, says he lost about 40 pounds within months of surgery. He got rid of 60 pounds more over the next year after starting a regular exercise program, and is down to a manageable 220 pounds.
“It’s harder for extra weight to come on to me, and it’s easier for it to fall off than it used to be,” he says. In fact, he adds, he feels that his whole attitude toward food has changed for the better after his vagotomy. “I eat less food, eat it more slowly and enjoy it more.”
Once the vagus nerve is cut, it can’t be restored -- a potential drawback, because the reduced appetite and slowed digestion may no longer be required or even desirable once a patient attains a healthy body weight. And so some researchers are testing whether it’s possible to achieve the weight loss effects of vagotomy while keeping the vagus nerve intact.
The technique they are using is called vagal nerve blocking, which has been developed by St. Paul, Minn.-based EnteroMedics. A surgeon implants a matchbox-sized device in the patient’s side that sends a high-frequency electrical signal to the vagus nerve. The electrical signal effectively blocks the nerve, causing the same effect on appetite and digestion as a vagotomy, says Mark Knudson, the company’s chief executive. Turning off the signal restores vagus function, he adds.
This procedure is now being evaluated in a 300-patient placebo-controlled study underway at several U.S. research centers. Patients in both arms of the EnteroMedics-sponsored trial are implanted with the device. But it is not turned on in the placebo group.
“Vagal nerve blocking gets to the root of the problem to inhibit the hunger pains these patients have,” says Dr. Ninh Nguyen, a gastrointestinal surgeon who is leading the trial at the UC Irvine Medical Center.
One of Nguyen’s subjects, San Juan Capistrano resident Jeff Collins, 25, says he has lost about 20 pounds since he joined the trial in December at more than 300 pounds. Wearing the VBLOC device causes only mild discomfort, he says. And judging by the result, he thinks he is getting the therapy, not the placebo.
“I still love food, and still get hungry,” he says. “But I am eating healthier, and eating a lot less than I used to.”
Each has its downside
Both vagotomy and vagal nerve blocking have advantages and drawbacks. “With vagotomy, they snip something, and your anatomy is permanently altered,” Knudson says. “With our method, you are living a more normal life.”
“With the EnteroMedics approach, you carry a foreign object in your body that needs constant attention and could cause infection,” Lustig says. “Vagotomy doesn’t have those problems.”
Both treatments are done using a technique called laparoscopic surgery, which is much less invasive than most weight loss surgeries. Knudson estimates that VBLOC therapy will cost about as much as gastric bypass surgery (about $25,000, according to the National Institutes of Health). Vagotomy as it is done now would cost about $9,000, Lustig estimates. But costs could come down if an experimental technique for snipping the vagus nerve using sound waves, developed by EndoVx, turns vagotomy into a simple outpatient procedure. This has been tested on animals and will be tried on human patients next year, says William Aldrich, the company’s chief executive.
It isn’t yet known whether either procedure will have a lasting effect on body weight. The body’s ability to adapt to a weight loss therapy and find other ways to gain weight has doomed many initially promising anti-obesity drugs. VBLOC tries to prevent the body from adapting to it by using intermittent, rather than constant, blocking of the nerve, Knudson says. Since vagotomy can’t do this, obesity researchers such as Dr. Samuel Klein of the Washington University School of Medicine in St. Louis predict it may produce only temporary weight loss.
Lustig, however, cites earlier studies that found that weight loss from vagotomy was sustained for up to 25 years and says that most of his patients have not regained lost weight after 18 months.
Both approaches are being conducted only in clinical trials for now. If the VBLOC study goes well, the device is likely to get Food and Drug Administration approval within two to three years, Knudson says. Vagotomy, since it is a surgical procedure, does not need FDA approval, but the EndoVx device for snipping the vagus nerve would need to be approved, and this could take several years, Lustig says.
For now, the only really effective therapy for severe obesity is weight loss surgery, Schauer says. “But perhaps in five or 10 years we may have a minimally invasive procedure that is just as effective.”
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A more sympathetic strategy?
Disabling the vagus nerve slows down energy storage in fat tissue. Another surgery may make the body burn fat faster.
Such a procedure would target the sympathetic nervous system, which regulates fat burning -- as opposed to the parasympathetic nervous system (including the vagus nerve), which regulates energy storage. Some researchers believe that stimulating certain sympathetic nerves could promote weight loss by burning off more calories from fat tissue. “It is like getting the effect of exercise without having to do real exercise,” says Dr. Jiande Chen, a gastroenterologist at the University of Texas Medical Branch at Galveston.
Clinical evidence for this idea is lacking, Chen cautions, but indirect support comes from studies on dogs, cats, rabbits and other animals. For instance, in a 1998 study on hamsters at Georgia State University in Atlanta, Timothy Bartness and co-workers found that cutting the sympathetic nerves to part of an animal’s fat tissues prevented its body from burning up the energy stored there. Unlike the remaining fat tissues, the “denervated” tissue did not shrink even when food intake was decreased. This suggests that stimulating the nerves instead could have the opposite effect -- of promoting fat burning.
Inspired by this possibility, Brooklyn Center, Minn.-based Leptos Biomedical is building a pacemaker-like electronic device designed to stimulate sympathetic nerves in specific fat tissues in the body. In addition to shrinking these tissues, the therapy may cause patients to feel fuller and less hungry, says Kobi Iki, vice president of research at the company. Animal studies show that the method produces consistent weight loss, reduced food intake and an increase in the muscle-to-fat ratio, Iki says, and the company is currently preparing for human trials of the method.
Although much more speculative as a therapy for obesity than vagotomy or vagal nerve blocking, sympathetic nerve stimulation has a potential advantage over them. By allowing the surgeon to choose which sympathetic nerves to stimulate, it offers the possibility of targeted weight loss. Thus the technique could be used to get rid of “bad” fat around organs while sparing fat elsewhere in the body, according to Dr. Ken Fujioka, an endocrinologist and principal investigator of the VBLOC trial at Scripps Clinic in La Jolla, and a consultant for Leptos. “If you can target abdominal fat, that is really the Holy Grail right now.”
-- Chandra Shekhar
