ESPE Abstracts (2019) 92 FC8.1

Hypothalamic AgRP Neurons Drive Endurance in Food-restricted Mice

Maria Consolata Miletta, Tamas L. Horvath


Yale University School of Medicine, New Haven, USA


Diseases of food restriction, such as anorexia and bulimia nervosa, are psychiatric conditions with the highest mortality. It is not known how these disorders emerge and what determine mortality. Individuals with these disorders frequently engage in compulsive exercise. States of food restriction are associated with elevated activity of hypothalamic neurons that produce AgRP, which cells are crucial for feeding and can promote stereotypic behaviors.

Here, we interrogated whether these hypothalamic neurons are involved in sustained compulsive exercise during food restriction. Using a combined pharmacologic and genetic approach, we found that regardless of AgRP circuit activity, food-restricted animals engaged in compulsive exercise if a running wheel was available, but there was a positive correlation between AgRP circuit activity and exercise volume. Strikingly, animals with impaired AgRP circuitry died of exhaustion after few days of compulsive running, while those animals, in which we activated AgRP neurons daily, had significantly increased endurance of compulsive exercise compared to all other groups without lethality during the trial.

As a mechanistic cause of the involvement of AgRP neurons in endurance exercise, we found that these cells are crucial for proper mobilization of lipids from fat stores, a known determinant of endurance running.

These observations shed new light on a previously unsuspected organizational role of AgRP neurons in the regulation and dysregulation of complex behaviors via both neuronal and systemic actions with direct implications for psychiatric conditions such as anorexia nervosa.

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