Perspectives on Neuroscience and Behavior

Abstract

Anorexia nervosa (AN) is a severe life-threatening illness; it has the highest mortality rate of any psychiatric illness (mortality is 11-12 times higher and suicide 56 times higher than the general population) and only 50% have a full recovery. The central feature in AN, an intense fear of gaining weight, results in an abnormally low body weight (body mass index < 17.5) secondary to food restriction, vomiting, and use of laxatives and frequent engagement in excessive compulsive exercise. Hypothalamic agouti-related peptide (AgRP) neurons have a central role in driving food seeking by increasing appetite and decreasing metabolism and energy expenditure. Now, it has been found that altered AgRP circuit function during exercise in mice produces characteristics of AN that includes reduced food intake, compulsive exercise, and death. In an activity-based anorexia mouse model where mice voluntarily run, peripubertal mice (P36) with food restriction (which typically increases running) had no change in AgRP neuronal activity during running, but it was decreased following cessation of voluntary running and the decrease was greater when food was presented. In food-restricted mice with AgRP neurons ablated, running resulted in decreased caloric intake, weight loss, and death in 100% of mice by 3 days. Daily activation of AgRP neurons increased voluntary running and prevented death in food restricted mice. Sedentary mice and mice with AgRP neurons ablated had increased serum free fatty acids (FFA) during food restriction but running decreased FFA in mice with AgRP neurons ablated and providing a highfat diet prevented death during running in these mice. In addition, running increased compulsive marble burying which was decreased with a high-fat diet (Miletta and others 2020). Together, these findings demonstrate an impaired metabolic adaptive response to running in mice without AgRP neuron function that leads to death. This organizational role of AgRP neurons in mediating the peripheral response to exercise has implications for the management and treatment of AN. Obviously, increasing caloric intake and preventing excessive exercise in AN are central to effective treatment and prevention of death, and this can also reduce some of the compulsive behaviors leading to an improved behavioral adjustment. It is not known if there are intrinsic abnormalities in AgRP neurons in AN, but these findings clearly indicate that they are involved in preventing death from food restriction during exercise. Using this model, it may be possible to discover other factors that control AgRP neuron function that could be utilized to improve AN treatment.