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Issued: February 6, 2003
runews@rockefeller.edu
Contact: Joseph Bonner (212) 327-7900

Obesity not a personal failing, says leptin discoverer Jeffrey Friedman, but a battle against biology
Broad-based basic and clinical research program needed to better understand interactions of genes and environment

"Jack Sprat could eat no fat, his wife could eat no lean," goes the classic children's nursery rhyme, implying that Jack's trim figure and his wife's portly profile were a conscious choice, since "betwixt the two of them, they licked the platter clean."

But as Jeffrey M. Friedman, M.D., Ph.D., argues in a "Viewpoint" article in a special obesity issue of the journal Science published Feb. 7, obesity cannot be easily explained as simply a breakdown in willpower. Genes and environment, explains the Rockefeller University and Howard Hughes Medical Institute researcher, both play important roles in determining a person's body weight. He points put that "in general, environmental factors account for trends in a population over time, while genetic factors account for most of the differences in weight among individuals in present time.

"While answers are beginning to emerge as to why so many of us are obese, there can be no meaningful discussion on this subject until we resist the impulse to assign blame," writes Friedman, who led the laboratory team that discovered the obesity hormone leptin in 1995. "Nor can we hold to the simple belief that with willpower alone, one can consciously resist the allure of food and precisely control one's weight.

"Instead, we must look at the facts dispassionately and uninfluenced by the numerous competing interests that drive debate on this subject."

The facts, according to Friedman, are: increase in weight does not fully account for the increase in the incidence of obesity; the drive to eat is to a large extent hard-wired and differences in weight are genetically determined; and evolution exerts powerful forces that obese people need to fight in order to lose weight.

An understanding of how genes and environment interact to cause obesity, Friedman urges, requires a broad-based research program that investigates not just the genes but how they interact with the environment.

With nearly one-third of the U.S. population obese an increase of 10 percent in the last decade public health officials have been sounding an alarm, since obesity carries an increased risk for heart disease, high blood pressure and diabetes. And even more disturbing is the increased incidence of type 2 diabetes in children which public health officials blame on the obesity epidemic in young adults. Friedman points out that although the incidence of obesity in the United States has increased from 23.3 percent in 1991 to 30.9 percent today, the weight of the average American has increased about only seven to 10 pounds, on the average.

Why does an incremental increase in the average weight have such a significant effect on the incidence of obesity?

As Friedman explains, the reported incidence of obesity is rooted in the definition of obesity, which is described by the body mass index, or BMI. BMI is a measure of body fat based on height and weight that applies to both adult men and women. (A BMI calculator can be found at http://nhlbisupport.com/bmi/bmicalc.htm/.) Obesity is diagnosed when BMI passes a defined threshold: People are said to be overweight if their BMI is greater than 25, and obese if their BMI exceeds 30.

According to Friedman, since obesity is defined as a threshold, an increase in average weight has a disproportionate effect on the increasing incidence of obesity.

Friedman suggests that there is a bright side: small, achievable decrease in the average weight of the U.S. population could have an enormous benefit to public health.

In addition, Freidman cites a statistical analysis of BMI trends by Katherine Flegal, Ph.D., an expert in the epidemiology of obesity and overweight at the U.S. Centers for Disease Control and Prevention, which shows that in addition to an increase in average BMI, the distribution of BMI in our population is also becoming increasingly skewed at the higher end.

"Thus in modern times, some individuals have manifested a much greater increase of BMI than others strongly," Friedman writes, "suggesting the possibility that in our population there is a subgroup that is genetically susceptible to obesity and a different subgroup that is relatively resistant."

Many factors have been cited as contributors to the rise in obesity: a shift in American eating habits toward more fast food, increased consumption of soft drinks, decreased physical activity and increased inactivity.

But even with these environmental changes, Friedman poses a basic question: how can anyone be thin in an environment where virtually everyone has unfettered access to calories?

The answer lies in the interaction of the environment with the biological system that our genes comprise.

In 1995, Friedman and his colleagues discovered the hormone leptin, which is produced by fat tissue and signals the brain when to stop eating. As body fat increases, more leptin is produced, which acts to reduce food intake. As body fat decreases, less leptin is produced, which stimulates food intake and reduces energy expenditure. Research by Friedman and other scientists has shown that genetic mutations that lead to a full or partial loss of leptin are associated with obesity in some humans.

In addition to leptin, Friedman and other scientists have identified a number of hormones and genes that play a role in appetite and weight. These hormones orchestrate the unconscious urge to eat, a basic biological drive that is difficult to fight with the conscious desire to eat less.

"Those who doubt the power of basic drives, however, might note that while one can hold one's breath, this conscious act is soon overcome by the compulsion to breathe," notes Friedman. "The feeling of hunger is intense and, if not as potent as the drive to breathe, is probably no less powerful than the drive to drink when one is thirsty.

"Who is it that can resist a drink of cold water when their lips are parched? This is the feeling the obese must resist after they have lost a significant amount of weight.

"The power of this drive is illustrated by the fact that, whatever ones motivation, dieting is generally ineffective in for achieving significant weight loss over the long term."

But what is the role of environment in all this? According to Friedman, genes that compose the biological system that regulates weight should be expected to vary depending on the environment due to intense selective evolutionary pressure.

In other words, people who lived when food was sporadically available - for example, hunters-gatherers -- benefited from genes that predisposed them to obesity, since "these genes would increase energy stores and provide a survival advantage during times of famine," Friedman says.

For those who lived in areas where the risk of starvation was low because of farming, domestication of animals and the ability to store food Western civilizations, for example the same genes that protected people from starvation may have exposed the obese to significant health consequences, such as diabetes and heart disease.

Modern-day humans, according to Friedman, "carry the genetic legacy of both environments.

"In modern times, obesity and leptin resistance appear to be the residue of genetic variants that were more adaptive in our previous environments," he says. "It may be that the obese carry the 'hunter-gatherer' genes and the lean carry the 'Western' genes.

"The lean carry genes that protect them from the consequences of obesity while the obese carry genes that are atavisms of a time of nutritional privation in which they no longer live," he continues.

Taken together, our genes and our environment collaborate to build a formidable barrier for those who want to lose weight.

"Obesity is not a personal failing," Friedman argues. "In trying to lose weight, the obese are fighting a difficult battle a battle against biology, a battle that only the intrepid take on and one in which only a few prevail."

Friedman is the Marilyn M. Simpson Professor at The Rockefeller University and an investigator at the Howard Hughes Medical Institute. His research is supported by the National Institute of Diabetes, Digestive and Kidney Diseases, part of the federal government's National Institutes of Health.