ons. Psychogenic theories for AN persist despite considerable evidence from careful neuroendocrine research that weight loss leads to the distinctive syndrome in both rats and humans (11, 22-25).
Hyperactivity is a primary symptom
The English and French physicians who independently described the syndrome in 1873 included hyperactivity as a primary symptom. Frances Gull wrote, “[t]he patient complained of no pain, but was restless and active. …it seemed hardly possible that a body so wasted could undergo the exercise which seemed agreeable.” His French counterpart, Charles Lasègue wrote, “…far from muscular power being diminished, this abstinence tends to increase the aptitude for movement. The patient feels more light and active…. …is never tired. ”
Although the DSM-5 authors assumed hyperactivity is secondary to desire to lose weight, prominent anorexia researchers maintain it is a core symptom (26). Casper pointed out that a level of energy greater than normal is measurably present in all patients at some time during the illness (32). This is important because relegating hyperactivity to secondary status has obscured the similarity between AN in humans and anorexia in animals.
Researchers searching for genes associated with longevity in yeast and mice have found a gene, Sirt-1, which turns on hyperactivity in starving mice and rats (33). Sirt-1 is a regulator involved in fatty acid oxidation and respiration; during famine it increases mitochondrial biogenesis and remodeling to become more efficient by increasing the proportion of respiration coupled to ATP production, reducing overall oxygen consumption and detoxifying the byproducts of increased metabolism(34). These changes transform ordinary mice into super mice, able to run over twice as long on a treadmill before collapsing in exhaustion (35)
Calorie restriction can lead to increased mitochondria in humans as well (36). Perhaps this explains the expression in some sports that “the thinner is the winner.” In sports such as endurance cycling where performance weight is lower than training weight, athletes’ memoirs have described how coaches and players, perhaps unwittingly, elicit AN symptoms (37). The ability to develop AN in response to calorie restriction may have become a de facto requirement for elite competition. Ignorance about the actual cause of AN allows these practices to continue without debate.
The homogeneous phenomenology of AN points towards the biological mechanisms and structures involved in restricting food, hyperactivity and hallucinating body fat. It has been difficult for even the most articulate sufferers to explain the anguish of being asked to eat. People with AN often think obsessively about food and cook elaborate meals for others that they cannot bring themselves to eat. One patient said, “I know if I continue like this I will die, but eating is even more terrifying.”
Endocrinologists were first in noting that some appetite signals in AN are the opposite of normal starvation (38). In 2001 Akio Inui noted that while people with anorexia nervosa have high levels of hunger hormones they also have increased satiety and anorexigenic signaling (39). For example, a potent satiety signal, cholecystokinin, increases rapidly when underweight people with AN begin to eat, leading to queasy satiety along with gnawing hunger. Inui wrote, “This may explain why many anorexics cannot easily reverse their illness in contrast to simple starvation. It is possible that the mixed signals about satiety and desire to feed could contribute to the ambivalence about food, i.e., the dissociation that anorexics often display between reduced caloric intake and obsessive thoughts about food” (39, p. 623). Inui’s conclusions had no discernable impact on psychogenic theories for AN.
In the last decade functional magnetic resonance imaging (fMRI) from independent laboratories reported the same pattern of abnormal activation when subjects were asked to eat or imagine eating. Thinking about food stimulates excessive prefrontal cortical activity (40-43). The prefrontal corte