Are We Destined to Gain Weight?

Christian Vaisse, MD, PhD, studies weighty matters - the genetics of obesity. He has identified a mutated gene that is responsible for extreme obesity, at least in a rare and unfortunate few. Moreover, Vaisse, an endocrinologist and associate professor with the Diabetes Center at UCSF, has recently made a patentable discovery that may one day lead to new drug treatments. So, given his success, you might expect Vaisse to be overly optimistic about genetic fixes for fat. He's not. But there is hope in his caution.

Evolution Favors Fat

It can be tricky messing with the mechanism that sets the body's thermostat for storing energy as fat. It's called a lipostat.

"Lipo" means fat - as in liposuction. The lipostat establishes a set point for weight.

But if there is a set point for each of us, then why do almost all adults gain weight?

"The body matches food intake to energy expenditure," Vaisse says. "But like every biological system, it's not perfect."

Gaining a pound a year can turn a thin young adult into an overweight middle-aged one. And the lipostat only has to be off by a tiny fraction to drive that kind of weight gain.

"The system is built so that if it doesn't work, you eat too much," Vaisse says.

"From the standpoint of evolution, getting a little more food than you need is not a problem for growth, and it's not a problem for reproduction. Therefore, it's not a problem for survival."

On the other hand, running an energy deficit clearly does not favor survival. Ancient animals or people with genes that skewed their lipostats in that direction would be more likely to starve and fail to pass those genes down through later generations.

Targeting an Obesity Gene

Identifying a gene harboring a rare mutation sufficient to cause an animal or human to become very obese can lead to a better overall understanding of how biochemical pathways normally govern weight. This understanding in turn may lead to new ideas for how to design better drugs to help control weight.

By studying a really fat strain of mice that had sprung up in a breeding lab, researchers discovered a key component of the lipostat - the hormone leptin - a little more than a decade ago.

Leptin, which helps curb appetite, circulates in the blood at levels roughly comparable to body fat. If you keep eating too much, rising leptin levels should dampen your appetite and help prevent more weight gain.

Leptin quickly rose to fame because when given to lab rodents, it caused them to lose weight, at least at first. But it ultimately proved disappointing as a weight-loss drug. Vaisse proposes that there are many feedback mechanisms in balance when it comes to controlling weight, appetite and energy expenditure. The system might not be easy to fool for long through manipulation of any one component.

Several years ago, in a very obese patient, Vaisse discovered a mutation in a gene that encodes a protein that acts downstream from leptin to help put the brakes on appetite. The protein - called MC4R - is a cell-surface receptor that receives signals from outside the cell and relays them to the cell's interior.

Rodent studies revealed that the protein is found only in certain cells within the hippocampus, a structure deep within the brain. When the mutation encoding the malfunctioning MC4R protein was engineered into mice, the rodents ate excessively and became fat.

Drugs designed to mimic the molecules that normally activate MC4R should lessen appetite. But mice became resistant to candidate drugs within hours, Vaisse says.

More recently, Vaisse has identified another mode of MC4R activation that appears to be switched on constantly at a modest baseline level regardless of food consumption or fat stores. This mode of MC4R activation might be more responsive to drugs aimed at amplifying the effect to further reduce appetite, Vaisse says.

Many Genes May Help Determine Weight

Only a few genes govern eye color, but when it comes to obesity, Vaisse does not expect any scientist to find a common variation in a single gene - or even in just a few genes - that is responsible.

Scientific efforts to find such genes should already have borne fruit, he suggests. Vaisse suspects that many genes may contribute in small ways to the tendency to put on weight.

In individuals who gain weight more easily, variations in several genes may be operating simultaneously to favor fat accumulation.

Even so, that does not mean that a different anti-obesity drug needs to be developed to target every molecular contributor to weight gain. Despite the difficulty in identifying molecules that may be targeted effectively, there is hope for eventual success.

After all, Vaisse observes, the drugs known as statins work well to lower cholesterol for most people. This is true even though there are a variety of genes for which some inheritable versions contribute to high cholesterol.

By Jeff Norris