November 2000 • Volume 6 Number 11
Nature vs. nurture
Is obesity grounded in genetics or behavior -- or both?
BY CINDY McCANSE
Seldom in medicine has the relationship between genetic predisposition and environmental influences been more ardently investigated than in obesity research.
Are patients, simply by virtue of their genotype, sentenced to a lifetime of struggling against weight gain regardless of their eating and exercise behaviors? Or should the rising prevalence of obesity in this and other developed countries be attributed to behavioral responses to changing environmental factors -- from fast food to the television remote control?
Apparently, the answer is both.
According to Raul Zimmerman, M.D., director of the Halifax Medical Center Family Practice Residency in Daytona Beach, Fla., and co-medical director of the center's weight management program, the genetic basis of obesity is best viewed in terms of what's known as the discordance hypothesis. Speaking at a Sept. 20 session on obesity at the AAFP Scientific Assembly in Dallas, Zimmerman put it succintly: "The problem is that we have old genes in a new environment."
Raul Zimmerman, M.D.
"The problem is that we have old genes in a new environment."Our genetic makeup, Zimmerman noted, originated in a harsh environment in which subsistence depended on hunting and gathering, physical activity was mandatory for survival and periodic famine was the norm. The human gene pool, he added, has not changed substantially since that time. Thus, in today's environment, where food is more plentiful and in most cases easier to obtain, those same genes favor obesity.
Using this concept as a starting point, researchers conducting studies of comparative body mass index values among twin pairs and other family members have estimated that genetics contributes to about 40 percent of obesity variance. Variations in prevalence according to demographic and/or socio-economic factors suggest a model in which susceptibility to obesity is largely a function of genetics, but the environment determines phenotypic expression.
Studies using animal models have helped identify gene loci that, in the presence of specific environmental variables, produce obesity. Recent advances in mapping the human genome have confirmed that some of these areas have homologues in humans.
Gregory Barsh, M.D., Ph.D., associate professor of pediatrics and genetics at Stanford University School of Medicine, Stanford, Calif., uses animal genetics as a model system to study human body weight regulation. He cited one example of a determinant of human obesity first hinted at by genetic studies in mice.
"MC4R, or melanocortin 4 receptor, is the gene identified to date that is a major contributor to human obesity," said Barsh. "As many as 5 percent of morbidly obese patients have been found to have an alteration in MC4R."
Using both mendelian and quantitative genetic approaches, researchers have now identified more than 200 genes and gene markers that contribute to human obesity. But that's just the beginning. Much still remains to be done to translate these findings into appropriate and effective prevention and treatment strategies.
Basically, Barsh said, genetics may serve two primary functions in helping obese patients.
"This is all hypothetical at this point," he noted, "but we may be able to identify patients who are deficient in a certain protein. Type 1 diabetes presents an excellent example in which patients are treated by replacing insulin." In much the same manner, he went on, "We may be able to use genetics to replace genes that are defective."
Also, Barsh added, clinicians could use genetics to reveal whether a patient's obesity is due to inappropriately high appetite or inappropriate peripheral utilization of nutrients. "If you can identify which of those mechanisms is responsible for a patient's obesity, you can target drug therapy specifically to that cause," Barsh said.
FP Report is published by the AAFP News Department.
Copyright © 2000 by American Academy of Family Physicians.
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