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able to track down the mutation in the obese mice and found that it blocked production of a particular protein hormone, which they named leptin. The leptin protein is only secreted by fat cells. When similar analysis was performed on the db mice, it was found that the disrupted db gene was responsible for encoding a protein that functions as a leptin receptor: When it binds circulating leptin at the cell surface, it sets in motion a biochemical cascade inside the cell. Most provocatively, the leptin receptor is expressed strongly on neurons in those areas of the hypothalamus that cause obesity or leanness when destroyed.
So with Friedman's key findings we now have a reasonable hypothesis for how the hypothalamus can sense body weight and use that information to maintain it within a narrow range. When weight is gained, the amount of body fat increases, and since fat cells secrete leptin in proportion to their mass, leptin levels will consequently rise. Leptin circulates in the blood and crosses into the brain, where it is sensed by leptin receptors expressed on neurons in the hypothalamus. Activation of those neurons by leptin suppresses appetite and increases energy expenditure. When weight is lost, the system works in the opposite direction: Less fat means reduced levels of circulating leptin, increased appetite, and reduced energy expenditure.
So far, the evidence that supports this hypothesis is quite promising. Leptin levels in the blood do indeed increase with weight gain and decrease with weight loss. Injections of leptin in obese mutant mice cause them to reduce food intake and lose weight (and these injections work even if tiny doses are delivered directly to the hypothalamus). Injections of leptin in db mutant mice have no effect, because there are no leptin receptors in the hypothalamus for the exogenous leptin to activate.
Of those people who are morbidly obese, less than 1 percent harbor DNA mutations that disrupt the function of the leptin gene—a low
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