Ketogenic Food Ameliorates Activity‐Based Anorexia of Adult Female Mice

ABSTRACT Objective Genome‐wide association studies implicate metabo‐psychiatric origins for anorexia nervosa (AN). There are two case reports totaling six adult females who experienced complete remission of AN following a treatment comprised of ketogenic diet (targeting metabolism) with ketamine infusions (targeting psychiatric origins), but no study has determined the efficacy of ketogenic diet, alone. We addressed this gap in knowledge, with exploration of potential molecular mechanisms, using an animal model. Method Adult C57BL6 female mice underwent 2 or 3 cycles of activity‐based anorexia (ABA1, ABA2, ABA3), an animal model of AN relapse, in which AN‐like maladaptive behaviors of hyperactivity and voluntary food restriction are elicited when wheel access is combined with food restriction. ABA was categorized as severe, based on weight loss ≥ 20%, food restriction‐evoked increase in wheel counts > 10,000/6 h, and crouching/grimace, and compared across two groups: (1) KG, fed ketogenic food continuously ( N = 25); and (2) CON, fed standard diet ( N = 28). Results 86% of CON versus none of the KG were crouching with grimace during ABA1. 93% of CON versus 11% of KG lost weight severely during ABA2 ( p < 0.001, 8% difference of group mean weights). Severe hyperactivity was prevalent among CON (86%) and rare for KG (4%) during ABA2 ( p < 0.001 on all food‐restricted days). ABA up‐regulated BDNF (brain‐derived neurotrophic factor) in the hippocampus of both groups but ketone body, β‐hydroxybutyrate, in urine was increased only among KG. Discussion Ketogenic diet may reduce severity of AN relapse through reduction of compulsive exercise, via mechanisms that are in addition to BDNF up‐regulation and involve β‐hydroxybutyrate.