This same decoupling of food intake and weight would also be demonstrated when researchers studied what are now known as dietary models of obesity. Certain strains of rats will grow obese on very high-fat diets, and others on high-sugar diets. In both cases, the animals will get fatter even if they don’t consume any more calories than do lean controls eating their usual lab chow. This same decoupling occurs in animals that are regaining weight after lengthy periods of fasting. “It doesn’t matter how long you food-deprive the animal,” said Irving Faust, who did this work in the 1970s; “the recovery of body weight is not connected to the amount of food eaten during the recovery phase.” And this same decoupling of calories and weight has also been made consistently, if not universally, in the recent research on transgenic animals, in which specific genes are manipulated.

What may have been the most enlightening animal experiments were carried out in the 1970s by physiologists studying weight regulation and reproduction. In these experiments, the researchers removed the ovaries from female rats. This procedure effectively serves to shut down production of the female sex hormone estrogen (technically estradiol). Without estrogen, the rats eat voraciously, dramatically decrease physical activity, and quickly grow obese. When the estrogen is replaced by infusing the hormone back into these rats, they lose the excess weight and return to their usual patterns of eating and activity. The critical point is that when researchers remove the ovaries from these rats, but restrict their diets to only what they were eating before the surgery, the rats become just as obese, just as quickly; the number of calories consumed makes little difference.

George Wade, the University of Massachusetts biologist who did much of this research, described it as a “revelation” that obesity could be brought on without overeating, just as Pennington had described it as revelatory that weight could be lost without undereating. “If you keep the animals’ food intake constant and manipulate the sex hormones, you still get substantial changes in body weight and fat content,” Wade said. Another consequence of removing the ovaries was that the rats hoarded more food in their cages, which is analogous to storing excess calories as fat. Infusing estrogen back into these rats suppressed the food-hoarding, just as it prompted weight loss. “The animals overeat and get fat,” said Tim Bartness, who worked on this research as part of his doctoral studies with Wade in the 1970s, “but they are overeating because they’re socking all the calories away into adipose tissue and they can’t get to those calories. They’re not getting fat because they’re overeating; they’re overeating because they’re getting fat. It’s not a trivial difference. The causality is quite different.”