Leptin-Signaling Failure Could Cause Obesity in White Men

By Barbra Rodriguez

Leptin keeps rats and mice slim. But to the chagrin of drug companies, many humans don't respond to extra doses of the hormone, which influences fat metabolism and serves as a natural appetite supressant.

Now a team of researchers including members from Washington University School of Medicine has evidence that drug developers might have better luck focusing their leptin-related efforts on white men. In a statistical study of 115 black and 99 white families, the researchers determined that middle-aged white men who share a particular version of the molecule that receives the leptin signal were fatter than other volunteers.

Fat cells produce leptin to tell the body it has enough energy in reserve and can stop storing fat and decrease appetite. Leptin does this by traveling in the bloodstream to the brain, where it interacts with the leptin receptor molecule in the hypothalamus. This part of the brain then sends out a message to the body to alter how fat is metabolized.

A modified version of the receptor that appears in some white men might not respond well to leptin so that these men might begin to accumulate excess fat. "There appears to be a good association in these men between a modification of the leptin receptor and fatness based on various measures," said Ingrid B. Borecki, Ph.D.

The article was published in the January 2000 issue of Journal of Clinical Endocrinology & Metabolism. Borecki, an associate professor of biostatistics, and Dabeeru C. Rao, Ph.D., director of the Division of Biostatistics, both at Washington University, were co-authors. The study was led by Yvon C. Chagnon, Ph.D., at Laval University in Quebec, and Claude Bouchard, Ph.D., who recently left Laval to direct the Pennington Biomedical Research Center at Louisiana State University in Baton Rouge, La.

Previous studies involving people with differing lifestyles and genetic backgrounds had come up with mixed conclusions about the importance of leptin signaling in weight gain and obesity.

In the current study, volunteers shared a similar sedentary lifestyle and were about to begin a 20-week exercise training program as part of the HERITAGE Family Study. The 214 families included 88 black parents and 231 of their adult children and 192 white parents and 330 of their adult children. Neither group differed significantly in the proportion of participants who were skinny, of normal weight or obese.

The researchers measured leptin levels in sedentary volunteers' blood. Fat levels also were assessed in six ways, including weighing volunteers under water to determine the proportion of body weight that was fat and measuring skin-fold thicknesses. Volunteers' DNA also was purified from blood samples for further analysis, using three different markers within the leptin receptor.

All the receptor versions were present in blacks and whites. However, only white volunteers who inherited one particular version, Q223R, tended to carry extra weight for their height, a measure of fatness called the body-mass index. A closer look revealed that white fathers were most likely to carry extra fat when they had the seemingly unlucky version of the leptin receptor. This finding held true for five of the six measures of fatness.

Getting a grip
The Q223R receptor and the other versions studied interact with leptin the way a pair of tongs latches onto an ice cube. Because Q223R differs in a region equivalent to the end of one tong, Borecki suspects that this receptor doesn't grab leptin as well. "If the receptor were the right shape, it should have no difficulty attaching to leptin and allowing its biological actions to occur," Borecki said.
Women have a different hormonal environment than men, or there may be other genetically based differences that help protect them from weight gain if they have Q223R, Borecki noted. Black men who have Q223R also may overcome this drawback because of genetic differences that give them an advantage over their white counterparts. "This really goes to show you that the systems that govern obesity in humans are fairly complicated," Borecki said.

Why are white male children spared, though? Borecki suspects they aren't. They might overcome their genetic drawback because they are more active than their fathers. Some of the younger children participating also might have been undergoing growth spurts and hormonal changes that could obscure the pattern of results found in the adults.

Future studies that involve white men ages 25 and older should help clarify whether they share their fathers' propensity to put on the pounds. Because leptin also helps control how the body uses energy, the hormone's ability to influence metabolism in general also is under intense investigation. Borecki noted that the current study already has helped clarify the leptin story, though. She added, "Once we get a grip on a handful of factors that affect weight gain and study all of them in a collection of families, I think a fascinating picture is going to emerge."

SOURCE/REFERENCE: Washington University in St. Louis Record, 6th April 2000.