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Miletta, MC;Iyilikci, O;Shanabrough, M;estan-Pea, M;Cammisa, A;Zeiss, CJ;Dietrich, MO;Horvath, TL;
Hypothalamic agouti-related peptide (AgRP) and neuropeptide Y-expressing neurons have a critical role in driving food intake, but also in modulating complex, non-feeding behaviours1. We interrogated whether AgRP neurons are relevant to the emergence of anorexia nervosa symptomatology in a mouse model. Here we show, using in vivo fibre photometry, a rapid inhibition of AgRP neuronal activity following voluntary cessation of running. All AgRP neuron-ablated, food-restricted mice die within 72 h of compulsive running, while daily activation of AgRP neurons using a chemogenetic tool increases voluntary running with no lethality of food-restricted animals. Animals with impaired AgRP neuronal circuits are unable to properly mobilize fuels during food-restriction-associated exercise; however, when provided with elevated fat content through diet, their death is completely prevented. Elevated fat content in the diet also prevents the long-term behavioural impact of food-restricted fit mice with elevated exercise volume. These observations elucidate a previously unsuspected organizational role of AgRP neurons, via the mediation of the periphery, in the regulation of compulsive exercise and its related lethality with possible implications for psychiatric conditions, such as anorexia nervosa.