Good Calories, Bad Calories (67 page)

In 1934, the Harvard physiologist Milton Lee reported that when rats had their pituitary glands removed and were injected with growth hormone (a product of the pituitary gland), they gained “significantly more weight” than their untreated littermates, even when eating identical quantities of food. The implication was that the weight gain was caused by the effect of growth hormone, independent of calorie consumption. The treated rats grew heavier, larger, and more muscular, Lee reported; the rats found the calories to do so by consuming what fat they had and by expending less energy in physical activity.

As for genetical y obese mice, it is invariably the case, as Jean Mayer discovered in the early 1950s, that these animals wil fatten excessively regardless of how much they eat. Their obesity is not dependent on the number of calories they consume, although al owing them to consume excessive calories may speed up the fattening process. “These mice wil make fat out of their food under the most unlikely circumstances, even when half starved,”

Mayer had reported. And if starved sufficiently, these animals can be reduced to the same weight as lean mice, but they’l stil be fatter. They wil consume the protein in their muscles and organs rather than surrender the fat in their adipose tissue. Indeed, when these fat mice are starved, they do not become lean mice; rather, as Wil iam Sheldon might have put it, they become emaciated versions of fat mice. Francis Benedict reported this in 1936, when he fasted a strain of obese mice. They lost 60 percent of their body fat before they died of starvation, but stil had five times as much body fat as lean mice that were al owed to eat as much as they desired.

In 1981, M.R.C. Greenwood reported that if she restricted the diet of an obese strain of rats known as Zucker rats (or fa/fa rats in the genetic terminology), and did it from birth onward, these rats would actual y grow fatter by adulthood than their littermates who were al owed to eat to their hearts’

content. Clearly, the number of calories these rats consumed over the course of their life was not the critical factor in their obesity (unless we are prepared to argue that eating fewer calories induces greater obesity). What’s more, as Greenwood reported, these semi-starved Zucker rats had 50 percent less muscle mass than genetical y lean rats, and 30 percent less muscle mass than the Zucker rats that ate as much as they wanted. They, too, were sacrificing their muscles and organs to make fat.

The most dramatic of these animal obesity models is known as hypothalamic obesity, and it served as the experimental obesity of choice for researchers from the 1930s onward. It also became another example of the propensity to attribute the cause of obesity to overeating even when the evidence argued otherwise. The interpretation of these experiments became one of a half-dozen critical turning points in obesity research, a point at which the individuals involved in this research chose to accept an interpretation of the evidence that fit their preconceptions rather than the evidence itself and, by so doing, further biased the perception of everything that came afterward.

The hypothalamus sits directly above the pituitary gland, at the base of the brain. It is hard-wired by the nervous system to the endocrine organs, which al ows it to regulate the secretion of hormones and thus al physiological functions that themselves are regulated hormonal y. Tumors in the hypothalamus have been linked to morbid obesity since 1840, when a German physician discovered such a tumor in a fifty-seven-year-old woman who had become obese in a single year. The manifestation of these tumors can be both grotesque and striking. Stylianos Nicolaidis of the Col ège de France recounted the story of being driven to study obesity as a young physician in 1961, when a forty-eight-year-old woman was referred to his hospital for tests after gaining thirty pounds in a single month. He never got a chance to do the tests, however, because she literal y choked to death over the hospital dinner.

“She was eating so fast that she swal owed down the wrong pathway and suffocated,” Nicolaidis said. “When I performed the autopsy, I cut the brain in sections and found two very, very tiny metastatic tumors in the hypothalamus.”

Because of the proximity of the hypothalamus to the pituitary gland—the two together are known as the hypothalamic-pituitary axis—a question that haunted this research in its early years was which of these two regions played the dominant role in weight regulation. Researchers had managed to induce extreme corpulence in rats, mice, monkeys, chickens, dogs, and cats by puncturing their brains in this pituitary-hypothalamic region. The controversy was definitively resolved in 1939 by Stephen Ranson, who was then director of the Institute of Neurology at Northwestern University and perhaps the leading authority on the neuroanatomy of the brain, and his graduate student Albert Hetherington. The two demonstrated that it was, indeed, the hypothalamus, not the pituitary, that regulated adiposity in the rats; lesions in a region cal ed the ventromedial hypothalamus (VMH) would induce corpulence even in those animals that had their pituitary glands removed.

John Brobeck, a Yale researcher who had done his Ph.D. work with Ranson, was the first to propose a mechanistic explanation for the phenomenon.

Brobeck had replicated Hetherington’s experiments in his Yale laboratory and then read Newburgh’s articles arguing a perverted appetite as the cause of obesity. Now Brobeck perceived his research as providing experimental confirmation in laboratory animals of Newburgh’s hypothesis. The hypothalamic lesions, Brobeck argued, served to damage what amounted to a center of hunger regulation in the hypothalamus. The lesions made the rats hungry, and so the rats over ate and grew obese. He would later write about his astonishment at how voraciously these surgical y lesioned rats ate. Because obesity in most of his rats (but not al ) appeared only after the rats began eating ravenously, Brobeck reasoned incorrectly that “the laws of thermodynamics suggest that…food intake determines weight gain.” Brobeck coined the term hyperphagia to describe the extraordinary hunger manifested by these animals, and hyperphagia would become the accepted technical term for a perverted appetite that leads to obesity.

The alternative hypothesis, that the obesity in these animals was a disorder of fat metabolism, came from Ranson and Hetherington. Whereas Brobeck interpreted his argument in the context of Newburgh’s beliefs, Ranson interpreted his from the context of thirty years of brain research. Some of the lesioned animals ate voraciously, Ranson noted, which might have been due to hunger alone, but others ate normal y and stil grew obese. (Several of Brobeck’s rats also grew obese while eating no more than lean rats did, but Brobeck dismissed their relevance to his overeating hypothesis on the basis that some other effect “related to the feeding habits” of these animals might be responsible.*107 ) Ranson also noted “the tremendously decreased activity of these obese rats.”

Ranson argued that Brobeck’s hyperphagia hypothesis missed the bigger picture. “Insistence upon the primary importance” of either overeating or inactivity “would in al probability represent oversimplification of the problem, and this for at least two reasons,” Ranson wrote.

In the first place, the two factors are complementary in their effect upon body weight. Both would tend to increase it. A very sedentary life, combined with a high caloric intake would seem to be an ideal combination for building up a thick panniculus adiposus [layer of fat]. Secondly, these two factors may be only symptomatic, and not fundamental. It is not difficult to imagine, for example, a condition of hidden cel ular semistarvation caused by a lack of easily utilizable energy-producing material, which would soon tend to force the body either to increase its general food intake or to cut down its energy expenditure, or both.

Damage to the ventromedial hypothalamus caused a defect that directed nutrients away from the tissues and organs where they were needed for fuel and into the fat tissue, Ranson argued. It made the animals more lipophilic. This reduced the supply of fuel to the other cel s of the body and so caused “hidden cel ular semistarvation,” or what Astwood later cal ed “internal starvation.” That in turn led to the voracious hunger—hyperphagia—that Brobeck had considered the primary defect. As long as nutrients continued to be channeled into fat and away from the cel s of other tissues and organs, the animals would remain hungry. If they couldn’t satisfy this hunger by eating more—when their food supply was restricted, for instance—they would respond by expending less energy.

Brobeck’s scenario—that the primary role of the ventromedial hypothalamus is to regulate food intake—would survive into the modern era of obesity research, but Ranson’s insights were far more profound. Only Ranson could explain al the observations, and he did so based on an ongoing revolution in the understanding of the brain, and particularly the role of the hypothalamus. This was Ranson’s expertise. The hypothalamus is the “concertmaster” of homeostasis, as Time wrote in 1940, reporting on a two-day conference dedicated to discussing the “orchestral effects” of the hypothalamus and paying tribute to Ranson, who had done much of the research.

Just before Ranson and Hetherington took to inducing corpulence in rats, Ranson had studied the hypothalamic regulation of fluid balance. This influenced his interpretation of the later research. Our bodies conserve fluids and water, just as they do fuel. Even our saliva and gastric juices are reabsorbed and reused. Just as damage to the ventromedial hypothalamus can induce obesity, damage elsewhere in the hypothalamus can induce diabetes insipidus. The symptoms of this rare condition are excessive urination and a tremendous and constant thirst. These symptoms appear in uncontrol ed diabetes mel itus as wel , but in diabetes insipidus, insulin secretion is not impaired, so blood sugar and fat metabolism remain regulated and no sugar appears in the urine.

The similarities between diabetes mel itus and diabetes insipidus had led Ranson and other physiologists to conclude that the homeostatic regulation of fluid balance was akin to that of blood sugar. That both diabetes insipidus and obesity could be caused by hypothalamic lesions informed Ranson’s interpretation of the underlying disorders. In the case of diabetes insipidus, the lesions inhibit the ability of the kidneys to conserve water by suppressing the secretion of an anti-diuretic hormone that normal y works in the healthy animal to inhibit urination. This failure in the homeostatic regulation of fluids causes the kidney to excrete too much water, and that leads to a compensatory thirst to replace the fluid that’s lost.

The same cause and effect are evident in Type 1 diabetes mel itus. The inability of diabetics to utilize the food they eat, and particularly the carbohydrates, results in a state of starvation and extreme hunger. Diabetics also urinate more, because the body gets rid of the sugar that accumulates in the bloodstream by al owing it to overflow into the urine, and this is why diabetics wil be abnormal y thirsty as wel .

Lesions to the ventromedial hypothalamus can induce tremendous hunger and cause obesity, but now Ranson considered it naïve to assume that the hunger caused the obesity. Rather, the hunger was another consequence of a breakdown in homeostasis—the loss of calories into the fat tissue. This is why the animals get fat even when they aren’t al owed to satisfy their appetite. And this is why these lesioned animals are always hungry, at least until they put on enough fat so that the excess counteracts the damage caused by the hypothalamic lesion. Sedentary behavior is another way their bodies compensate for the loss of calories to the fat tissue. As Ranson perceived it, both hunger and physical inactivity are manifestations of the internal starvation of the tissues. These are the ways that the homeostatic regulation of energy balance compensate for the loss of nutrients into the fat tissue.

It’s hard to avoid the suggestion that one major factor in how this research played out was the preconceptions of the investigators and their urge to make a unique contribution to the science. Ranson had suggested that al the more obvious manifestations of hypothalamic lesions were the consequences of a primary defect in the homeostatic control of energy balance that made the animals accumulate excessive fat in the adipose tissue. Brobeck and the other investigators who took to studying hypothalamic obesity would conclude that whatever phenomenon they happened to find most remarkable in their own postoperative rodents was the critical factor, or at least a critical factor, requiring intensive investigation. By doing so, as Ranson had cautioned in the early 1940s, they oversimplified the physiology and only directed attention away from the fundamental problem. Jean Mayer, for instance, would discuss hypothalamic obesity in the plural—as the “classic type of experimental obesities”—and he would say that one such obesity was caused by lack of physical activity, as in his mice. Philip Teitelbaum, who did his research as a doctoral student at Johns Hopkins in the early 1950s, observed that VMH-lesioned rodents, at the peak of their obesity, became finicky eaters, and he concluded that this was an obvious manifestation of the behavior of taste aversion. This observation established his reputation in the field and also the common belief that the ventromedial hypothalamus controls food preference, too, and the motivation to 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 col eague 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 I raging and his adviser gone, Hetherington left Northwestern to do research for the U.S. Air Force. This left Brobeck, stil 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