If this hypothesis of hunger, satiety, and weight regulation is correct, it means that obesity is caused by a hormonal environment—increased insulin secretion or increased sensitivity to insulin—that tilts the balance of fat storage and fat burning. This hypothesis also implies that the only way to lose body fat successfully is to reverse the process; to create a hormonal environment in which fatty acids are mobilized and oxidized in excess of the amount stored. A further implication is that any therapy that succeeds at inducing long-term fat loss—not including toxic substances and disease—has to work through these local regulatory factors on the adipose tissue.

If the principal effect of a drug, for example, is to suppress in the brain the desire to eat, and thus reduce food consumption, then the body will perceive the consequences as caloric deprivation and compensate accordingly. Energy expenditure will be reduced, and weight loss will be temporary at best. On the other hand, any drug that works locally on the fat cells to release fatty acids into the circulation will inhibit hunger because it will be increasing the flow of fuel to the cells. This could also be the case for any treatment that appears to increase metabolism or energy expenditure. A weight-loss drug that works in the brain to increase metabolism will also increase hunger, unless it also works on the fat tissue to mobilize fatty acids that can supply the necessary fuel.

Consider nicotine, for instance, which may be the most successful weight-loss drug in history, despite its otherwise narcotic properties. Cigarette smokers will weigh, on average, six to ten pounds less than nonsmokers. When they quit, they will invariably gain that much, if not more; approximately one in ten gain over thirty pounds. There seems to be nothing smokers can do to avoid this weight gain.

The common belief is that ex-smokers gain weight because they eat more once they quit. They will, but according to studies only in the first two or three weeks. After a month, former smokers will be eating no more than they would have been had they continued to smoke. The excess of calories consumed is not enough to explain the weight gain. Moreover, as Judith Rodin, now president of Rockefeller University, reported in 1987, smokers who quit and then gain weight apparently consume no more calories than those who quit and do not gain weight. (They do eat “significantly more carbohydrates,” however, Rodin reported, and particularly more sugar.) Smokers also tend to be less active and exercise less than nonsmokers, so differences in physical activity also fail to explain the weight gain associated with quitting.