Animals maintain energy reserves in the form of lipid deposits (fat) - an evolutionary adaptation in response to periods of scarcity. The size of these deposits reflects the balance between energy intake as food and energy output as heat and work. Although humans vary greatly in the amount of energy stored in the form of lipid triglycerides in adipocytes (fat cells), obesity is defined medically as weighing at least 20 percent in excess of ideal body weight.
More than three in ten Americans are considered obese; the excess adipose
tissue puts them at increased risk for such medical problems as hypertension,
heart attack, stroke, diabetes, and some forms of cancer.
Obesity is often considered a psychological problem, but recent studies have shown that it is under strict physiologic control. It is now clear that the body's fat stores are regulated by a feedback loop: Adipose tissue emits a signal, in proportion to its mass, that is sensed by centers in the brain. As a result, food intake and energy expenditure are adjusted to maintain constancy of the size of the adipose tissue mass.
So precise is the control of the body's lipid energy reserves that they are maintained to within about 1 percent. (Otherwise, with a error rate of only 2 percent per year, a 150 lb. college student would end up weighing 500 lbs by age 65.)
The discovery of the physiological control of body weight began in the 1950's with the development of several strains of inbred mice that possessed heritable defects in the control of lipid storage. Mice carrying mutations of genes such as "ob" (for obesity) weigh as much as three times more than their normal counterparts.
In a clever experiment in the 1970s, Douglas Coleman used these mice, called "ob/ob mice," to infer the existence of a hormone that controlled the size of the body's lipid reserves. After surgically joining two mice together so that their blood circulations became partially fused, Coleman found that if a normal mouse is fused with an ob/ob mouse, the ob individual begins to revert to a more normal weight. It was as if the ob mouse were able to respond to an appetite-suppressing hormone produced by its normal partner that it could not produce itself. But here the problem stalled, for the experiments fell short of identifying the hormone, which evidently was present in the blood in minute, undetectable amounts.
This problem was solved when Jeffrey Friedman and his colleagues at The Rockefeller University isolated the mouse ob gene and its human equivalent in 1995 - the work of seven years. They applied recombinant DNA technology to chromosome 6 and found the site of the ob mutation and, therefore, the gene for obesity.
The cloning of the ob gene made it possible to produce large amounts of its protein product in the laboratory. When this protein was injected into ob/ob mice, the mice reduced their food intake, dropping 40 percent of their body weight during a month of daily injections. Normal mice also lost weight when injected with the protein -12 percent of their body weight and virtually all of their body fat in four days. With these findings, the protein product of the ob gene emerged as a hormone that emanates from adipose tissue and acts to regulate the size of the lipid deposits stored in the body. The new hormone was given the name leptin, from the Greek leptos, meaning thin.
Very recently, Louis Tartaglia and colleagues at Millenium Pharmaceuticals identified the receptor for leptin in the hypothalamus region of the brain. The finding of leptin and its receptor widens the entry point into a fuller understanding of obesity and to controlling - with exogenous agents - the size of the body's lipid energy reserves.
This, in turn, should provide preventive therapies for the widespread illnesses that are associated with obesity.
- David Dressler, Ph.D. and Huntington Potter, Ph.D.
(Photograph used with permission, Nature, Vol. 372: 425, 1994, cover.)