Good Calories, Bad Calories

eat. “Of course they overate,” he said of his obese rodents; “that’s why they became obese.” But he simultaneously acknowledged that they were also so inactive that they would fatten even without overeating.

In 1951, Brobeck and his colleague Bal Anand reported that lesioning a different region of the hypothalamus— the lateral hypothalamus—would induce rats to stop eating and lose weight and even die of starvation. Ranson’s lab had reported this phenomenon in rats, cats, and monkeys in the 1930s, but now Brobeck and Anand reinterpreted it to support Brobeck’s belief that the hypothalamus regulates eating behavior. Brobeck proposed that the lateral hypothalamus is a “feeding center” that motivates animals to eat, and the ventromedial hypothalamus works as a “satiety center” to inhibit eating.

In August 1942, just three months after Ranson and Hetherington published their research, Ranson died of a heart attack. If there was a single event that derailed the course of obesity research in the United States, this may have been it. With World War II raging and his adviser gone, Hetherington left Northwestern to do research for the U.S. Air Force. This left Brobeck, still a medical student at the time, as the leading authority on these experiments, and so it was Brobeck’s emphasis on overeating—hyperphagia—as the cause of the obesity in these brain-damaged animals that dominated thinking in the field, despite its inability to explain the observations. Though later editions of Ranson’s textbook The Anatomy of the Nervous System would continue to refer to the ventromedial hypothalamus as a regulator of fat metabolism, the investigators writing about human obesity would refer to the VMH as a regulator of hunger and ingestive behavior.

Once human-obesity research became the domain of psychologists and psychiatrists in the 1960s, studies of hypothalamic obesity left behind once and for all the greater context of homeostasis and the use and storage of metabolic fuels, and focused instead on how Brobeck’s dual centers of the hypothalamus allegedly regulate eating behavior. This served to further the conviction that defects in this region of the brain cause overeating, and overeating causes obesity. Hunger, and the overeating that accompanies it, would be considered exclusively a psychological phenomenon, not a physiological one. (Because these psychologists would consider eating behavior to be the subject of their research, they would often screen their animals after surgery and those that didn’t eat voraciously would be “discarded.” They would then omit these animals from their subsequent analyses, even if the discarded animals became obese as well.) Hunger was something that occurred only in the head, and so it could be decoupled from the needs of the body, at least with sufficient willpower.

Animal research continued to confirm Ranson’s hypothesis, even though its author had died, no matter whether the fattening was induced by hypothalamic lesions, genetic defects, or as the naturally occurring seasonal weight gain of hibernators. In 1946, for example, the Johns Hopkins physiologist Chandler Brooks reported that his albino mice become “definitely obese” after VMH lesions, and that they gained six times as much weight per calorie of food consumed as normal mice. In other words, it wasn’t how much these mice ate that determined their ultimate weight, or the number of calories, but how these calories were utilized. They were turned into fat, not used for fuel.

Though Brooks reported that he could prevent his albino mice from growing obese, he could do so only by imposing “severe and permanent” food restriction. If he subjected them to “long continued limitation of food,” the animals would lose some weight, but they would never lose the drive to fatten or the hunger that went with it. Periods of fasting, Brooks noted, were “followed by an augmentation of appetite and development of a greater degree of obesity than had been attained before fasting.” And so Brooks’s lesioned mice, as Hilde Bruch might have noted, were acting exactly like normal healthy humans and obese humans after a semi-starvation diet. These VMH lesions also resulted in changes in the reproductive cycles of the animals, and in their normal nocturnal eating patterns, which Ranson and Hetherington had also reported; once the animals became obese, they slept more than normal animals, all of which suggested that the VMH lesions had profound effects on the entire homeostatic system and could not be written off as simply affecting hunger and thus food intake.

When physiologists began studying animal hibernation in the 1960s, they again demonstrated this decoupling of food intake from weight gain. Hibernating ground squirrels will double their body weight in late summer, in preparation for the winter-long hibernation. But these squirrels will get just as fat even when kept in the laboratory and not allowed to eat any more in August and September than they did in April. The seasonal fat deposition is genetically programmed—the animals will accomplish their task whether food is abundant or not. If they didn’t, a single bad summer could wipe out the species.

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.”

One critical idea here is that survival of a species is dependent on successful reproduction, and that in turn depends first and foremost on the availability of food. Fat accumulation, energy balance, and reproduction are all intimately linked, and all regulated by the hypothalamus. This is why food deprivation suppresses ovulation, and why the same kind of hormonal control of reproduction ensures that herbivores, such as sheep, tend to give birth in the springtime, when food is available. The link between food availability and reproduction was something that Charles Darwin had also observed: “Hard living…retards the period at which animals conceive,” he wrote.

The lesson of these animal experiments is that understanding energy balance and weight control requires Claude Bernard’s harmonic-ensemble perspective of homeostasis: an appreciation of the entire organism and the entire homeostatic web of hormonal regulation. “Fertility is linked to food supply, physical exercise involved in foraging for food and avoiding predators, and energy expenditure associated with temperature regulation and other physiological processes,” Wade explains. These functions are controlled by a tight orchestration of both sex hormones and those hormones that control the “partitioning and utilization of metabolic fuels,” and this is