The phenomena of hunger and satiety have been the running subtext of all our discussions of obesity: the “persistent clamor of hunger” that attends semi-starvation diets; the absence of hunger during fasting and carbohydrate restriction; the question of whether insulin works as a fattening hormone or a hunger hormone when used to treat anorexia. And then, of course, there is the association of hunger, or at least positive caloric balance, with weight gain. If there’s one thing the law of energy conservation does indeed tell us, it’s that anything that works to increase or decrease our body mass must have compensatory effects on the balance of calories consumed and calories expended. Thus, any viable hypothesis of obesity must also be a hypothesis of hunger and satiety, and perhaps, as Alfred Pennington noted, of energy expenditure as well.

The study of human obesity, however, has included only a few vague conceptions of the physiological underpinnings of hunger and satiety. One common assumption is that when the stomach is empty it contracts, and that signals hunger. By this logic, dietary fat contributes to satiety by prolonging the drainage of nutrients out of the stomach. Another assumption is that hunger is a sensation that exists in the brain, having little or nothing to do with the immediate metabolic needs of the body itself. Though many obesity researchers will reflexively disagree with this statement, it is essential to the conventional wisdom—that the ability to remain indefinitely on a calorie-restricted diet is a matter of willpower, and the failure to remain on such a diet is a failure of character. Once the pursuit of a therapy for obesity left physiology and biochemistry behind and became a subdiscipline of psychology and psychiatry, and once it was “established” that the only way to lose weight, as Melvin Konner suggested, is to grow accustomed to feeling hungry, the natural focus of virtually all obesity research became, and has remained, the brain.

By the early 1970s, a handful of hypotheses had been proposed to explain how the brain might induce hunger and satiety, and in turn regulate weight by limiting caloric consumption to match expenditure. Two received the most attention and have entered the textbooks as the most likely explanations. Both hypotheses date to the 1950s; neither took into account the evolving research on insulin, insulin resistance, and fat metabolism. Both had conspicuous deficiencies that would be overlooked.