Research provides clues to obesity's cause

Apr 13 2006

Hot fudge sundaes and french fries aside, new research suggests obesity is due at least in part to an attraction between leptin, the hormone that signals the brain when to stop eating, and a protein more recently associated with heart disease.

Reporting in Nature Medicine, University of Pittsburgh researchers provide evidence that C-reactive protein (CRP) not only binds to leptin but its hold impairs leptin's role in controlling appetite.

The results may help explain why obese people have so much trouble losing weight as well as point to a different target for the pharmaceutical treatment of obesity.

"There's been a lot of interest in leptin as a means to curb appetite and reduce weight but clinical trials have had disappointing results. Our studies suggest an approach that should be further studied is one that disrupts the interaction between leptin and CRP, thereby restoring leptin's ability for signaling. We need to better understand how this interaction works and investigate the underlying mechanisms involved," said Allan Z. Zhao, Ph.D., assistant professor of cell biology and physiology, University of Pittsburgh School of Medicine, and the study's senior author.

Leptin is secreted by fat - the more fat, the more leptin - yet it is named for the Greek word leptos, which means "thin." In a region of the brain called the hypothalamus, leptin binds to receptors residing on the surface of neurons, setting off signals that tell the brain to stop eating and the body to expend energy by burning calories. While obese people produce much higher levels of leptin than thin and normal-weight individuals, they are somehow resistant to its effects. Dr. Zhao and his co-authors believe the binding of CRP to leptin may be the reason this is so. Their argument seems all the more plausible since CRP also is elevated in obese people. CRP, which is produced by the liver and typically rises as part of the immune system's inflammatory response, is gaining favor as a marker for hypertension and heart disease risk, known complications of obesity.

"We know that CRP binds to leptin, and this impairs its signaling, but we don't know how this is so. It may be that the coupling of the two makes crossing the blood-brain barrier difficult, or it may be that as a package it can't bind to leptin receptors in the brain," suggested Dr. Zhao.

Dr. Zhao and his collaborators sought to find factors normally circulating in blood that could inhibit leptin. CRP was the most potent of the five serum leptin-interacting proteins they identified.

In one set of studies, the researchers delivered human leptin continuously for six days into mice with receptors for leptin but without the ability to produce it. As expected, the plump mice ate less and lost weight, and their blood glucose levels normalized. Infusions containing both leptin and high doses of CRP blocked the action of leptin. The mice continued feasting, getting even fatter, and were no longer protected against diabetes. Giving CRP alone affected neither food intake nor body weight.

In a different experiment, the researchers found that when exposed to leptin, human liver cells increased their expression of CRP, suggesting that appetite may be regulated through a feedback loop that includes the liver in addition to the brain and fat cells that secrete leptin.

One of the many questions yet to be answered is whether too much fat increases CRP or if it's the high levels of CRP that make one fat. Dr. Zhao and his team are continuing their laboratory studies but they also plan to follow the outcomes of obese patients who are being treated with statin drugs, such as Lipitor and Zocor, for high cholesterol. Recent studies have found that statin drugs lower levels of CRP as well. Working with David E. Kelly, M.D., professor of medicine and director of the Obesity and Nutrition Research Center at the University of Pittsburgh and a co-author of the current paper, Dr. Zhao hopes to learn if such drugs might also help in reducing weight.