Brain, hormones keys to fighting fat

by Amanda Hughes

As U.S. waistlines continue to grow, Americans search desperately for answers to lose weight -- diet books, dusty gym shoes, fad drugs and even hypnosis.

Turns out, the answer was in your head all along.

Researchers at the Obesity Research Center, part of UC's Genome Research Institute, are leading the way in discovering how hormones from the stomach talk to the brain, informing our organs how hungry we are, what nutrients we need and how much energy to store. The hormone pattern and signals sent from the stomach to the brain, called the gut-brain axis, create a "remote control" for metabolism.

Matthias Tschoep, one of several UC professors involved in the project, believes the findings can lead to better drug-treatment options to fight obesity by allowing researchers to manipulate the hormones and messages received by the brain.

Although research has focused mainly on a new hormone called ghrelin, Tschoep says many hormones communicate with the brain in a complex pattern of information exchange. The brain then directs the other organs accordingly, telling them how much fat to store, how to process sugar and whether to speed up or slow down metabolic rates.

"There are probably dozens of hormones and factors and signals coming at any given moment from our periphery -- our fat stores, our intestine, our pancreas, our liver, probably our muscles, to inform the brain of what is going on. I think that integrated pattern of all those signals at any given time is key to what the brain then does to our metabolism and hunger sensations."

Those hormonal patterns are hard-wired to help us survive, Tschoep says. Our ancestors were hunters and gatherers who didn't always know where their next meal was coming from or how long winter would be. So their bodies adapted, developing mechanisms to store as much energy and fat as possible to help them survive leaner times.

"Now, for about the last 100 years or so, this important system has turned against us. We have too much fat, too much food, too many easy ways to regulate our temperature," Tschoep says. "So our bodies just keep storing energy, and we all gain weight, and gain more weight, and so on."

Obesity is a serious health epidemic in the United States. According to the American Obesity Association, 127 million American adults are overweight; 60 million Americans are considered obese, and another 9 million are morbidly obese. Tschoep stresses that obesity leads to other serious health conditions, as well, particularly diabetes. For the first time, life expectancy for the current generation is lower than it was for the previous generation. Tschoep largely attributes this statistic to the rise in metabolic diseases.

Current drugs on the market, Tschoep says, target the fat stores in the human body, a method that usually comes with toxic side effects. "But if we can cheat the brain into thinking we are already full, the brain will do the job for us naturally, at an enhanced level, to do what we want it to do -- be less hungry, get rid of some of the fat."

Critics argue it's impossible to create a drug that will effectively block all the hormone signals between the brain and stomach because there are simply too many -- food intake is so vital to human survival that our bodies send every signal possible to make sure messages about how much we're eating are received by the brain.

"My answer to that is to highlight another area where researchers have been told the same thing. Fifty or 60 years ago, scientists were looking for a drug to act as a contraceptive. They were told this is so important, and there are so many pathways making sure we reproduce, that you can't block fertility.

"They were successful by changing hormonal patterns, by replacing hormones, by giving certain hormone combinations, cheating the brain into believing a pregnancy is already there in a simplified way. And that worked."

To further understand hormonal pathways, Tschoep and his colleagues are working with UC surgeons and learning about bariatric, or gastric bypass, surgery. During the surgery, a significant portion of the stomach and small intestine is removed. The result is often substantial weight loss, up to 50 percent of a patient's body weight.

UC is one of the top centers for bariatric surgery in the country; however, Tschoep says there may be more to the success of the surgeries than the removal of the organs involved in digestion.

"We now believe that some of the very successful surgical approaches are actually doing something to the signaling systems that we're studying. If we can find out what those are, we could trigger them with the right drug.

"The surgery changes the way the stomach and brain communicate, and therefore, the way the brain then communicates with other organs. That's very likely the key and once we understand that, we can specifically modify the right pathways, we think, without surgery."

To continue their work, the Obesity Research Center recently received a substantial grant from Ethicon Endo-Surgery, a global medical-device company, to support the research during the next three years.

Randy Seeley, a fellow researcher involved in the project, says the team effort at the center creates a dynamic atmosphere. Twelve UC faculty members make up the research team at the Genome Research Institute. The team constitutes the second largest group in the country dealing with the biological aspects of obesity. Seeley believes the real-world impact of the research attracts both talented scientists and doctors as well as financial investment from companies like Ethicon.

"We're engaged in really relevant research," Seeley says. "Much of what we're doing now is what I call 'modeling the cure.'"

Until then, stay on that treadmill.

Links:

UC, Ethicon Endo-Surgery partner to fight obesity
American Obesity Association