If a person consumes more calories than he or she uses, they gain weight. If this continues over time, they become obese. All they should need to do, then, is reverse the whole process by restricting calories and/or expending more of them until a healthy body weight is restored.

If it were so simple, 5.5 million Canadians would not be obese. And the diet book industry would be bankrupt.

Unfortunately, eating too much does more than add pounds. It changes the chemistry of the brain, says Dr. William Colmers, Professor of Pharmacology at the University of Alberta.

"If you go on a diet when you're overweight or obese, in most cases your brain will think you're starving," says Dr. Colmers, who leads the CIHR Team in the Neurobiology of Obesity. "The brain has a set point, like a body weight thermostat, that's been shifted. That's why diets don't work."

Dr. Colmers uses electrophysiology and digital imaging in slices of rat and mouse brain to study how nerve cells use neurotransmitters to send and receive messages. He believes two key neurological components - the hedonic (reward) system that leads us to prefer ice cream over vegetables and the homeostatic (stabilizing) system that regulates the intake of calories in relation to the output of energy - are, essentially, out of sync.

"The homeostatic system is the body's way of keeping the balance between energy consumed and energy expended in check. It can regulate body weight with extreme accuracy - to within a slice of cucumber a day. But a high-fat or high-calorie diets can throw the homeostatic system off permanently."

In examining how the two systems interact, Dr. Colmers and colleagues are focusing on Neuropeptide Y (NPY), a short protein that acts as a chemical messenger and is involved in eating behaviour.

Sorting it out, however, will not be easy. NPY does much more than help regulate appetite. It also affects anxiety, sleep patterns and sexual arousal. Blocking it from fulfilling its function in triggering appetite could affect those other roles.

Other research efforts to manipulate neurotransmitters have met struggles. A drug called Acomplia, which inhibits the CB1 cannabinoid receptors in the brain to help curb appetite and promote weight loss, was linked it to "statistically, significantly increased suicidality" by an advisory panel to the U.S. Food and Drug Agency. In late 2008 the European Medicines Agency recommended a temporary suspension of marketing authorization of Acomplia for obese and overweight patients and it was withdrawn.

Dr. Colmers says it's important to take a larger look - studying how neurological systems interact. "Everything is tied into everything else in the brain," says Dr. Colmers. "There are very few things that work in isolation."

Medical science needs a better understanding of how the brain circuitry affects obesity, says Dr. Arya Sharma, Scientific Director of the Canadian Obesity Network.

"Most people fail to realize how complicated the behavior associated with obesity is. Dr. Colmers' work is a perfect example of how fundamental research can inform issues in clinical practice."

The Study

Dr. Colmers and his colleagues (see list below) are working on the theory that persistent activation of the hedonic (reward) system in the brain permanently changes defended body weight or "set point."

Using animal models, the researchers will investigate how prolonged stimulation of the hedonic system affects the homeostatic regulation that balances calories consumed with calories burned.

This five-year project will provide a clearer picture of how obesity changes the brain and what can be done to prevent or reverse it.

CIHR Team on the Neurobiology of Obesity

- Dr. William F. Colmers, Department of Pharmacology, University of Alberta (Principal Investigator)

- Dr. Alain Dagher, Montreal Neurological Institute, McGill University, Montreal (Co-PI)

- Dr. Alastair V. Ferguson, Department of Physiology, Queen's University, Kingston ON (Co-PI)

- Dr. Denis Richard, Merck-Frosst/CIHR Chair in Obesity, University of Laval, Quebec City, QC (Co-PI)

- Dr. Keith A. Sharkey, Department of Physiology and Biophysics, University of Calgary, Calgary AB (Co-PI)

Why do we get fat?

While environmental factors play a significant role in obesity, evolution shares a large part of the blame, says Dr. Colmers. He sketches a 13,000-years-ago scenario to make his case:

"Suppose you're a hunter-gatherer and you're out on the plains and living from hand to mouth. You stumble on a mastodon that's checked out and it's just waiting there to be eaten. There are maybe 20 people in your tribe. You can't freeze the mastodon because you don't have a freezer. There's no means of preserving food, so how do you carry it around with you? You eat it. You sit there and eat and eat and eat until it's gone or you've consumed as much as you possibly can. And then you carry it around in a sterile form as fat. This is a handy thing, this particular gene is a successful adaptation for survival."

Unfortunately, most of us are no longer hunter-gatherers and we are not living on a high-protein mastodon diet. We eat high-fat, high-calorie foods that we, sometimes, don't even get out of our cars to snare, let alone chase around the plains. Our lifestyles may have changed, but our genes haven't. We are still genetically predisposed to store the food, in the form of fat, to get us through the lean times.

Canadian Institutes of Health Research