Good Calories, Bad Calories

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 actually grow fatter by adulthood than their littermates who were allowed 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 genetically 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 allows it to regulate the secretion of hormones and thus all physiological functions that themselves are regulated hormonally. 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 Collège 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 literally choked to death over the hospital dinner. “She was eating so fast that she swallowed 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 called 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 surgically lesioned rats ate. Because obesity in most of his rats (but not all) 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.