Anorexia nervosa – a developmental perspective involving hypothalamic appetite regulation and microglia dysfunction

Anorexia nervosa (AN) is a psychiatric and metabolic disorder affecting 4% of females and 0.3% of men, with high heritability, mortality and chronicity, currently lacking biological markers for diagnosis and evidence-based pharmacological treatments.

Our purpose is to provide a novel route towards understanding of AN and to provide targets for better diagnosis of AN and its variants.

The aim is to explicate the function of microglia in AN, in particular in relation to the maintained starvation that is a prominent and critical part of the disorder.

Based on recent findings, we hypothesize that a genetic vulnerability in AN resides in a dysfunction of hypothalamic microglia, specifically their phagocytic capacity resulting in aberrant synaptic pruning of hypothalamic circuits regulating food intake, explaining the paradoxical response to starvation and maintained negative energy balance in AN.

We will determine in what way these circuits are perturbed by profiling of microglia and their interactions with hypothalamic neurons in reprogrammed patient-derived cells and anorectic mice models.

Successful completion of our aims will have important implications for advancing knowledge, diagnosis and treatment of AN, by identifying drug targets promoting renourishment, crucial in the early treatment phase and for long-term recovery.