Abstract
Food consumption is fundamental for life, and eating disorders often result in devastating or life-threatening conditions. Anorexia nervosa (AN) is characterized by a persistent restriction of energy intake, leading to lowered body weight, constant fear of gaining weight, and psychological disturbances of body perception. Herein, we demonstrate that SIRT1 inhibition, both genetically and pharmacologically, delays the onset and progression of AN behaviors in activity-based anorexia (ABA) models, while SIRT1 activation accelerates ABA phenotypes. Mechanistically, we suggest that SIRT1 promotes progression of ABA, in part through its interaction with NRF1, leading to suppression of a NMDA receptor subunit Grin2A. Our results suggest that AN may arise from pathological positive feedback loops: voluntary food restriction activates SIRT1, promoting anxiety, hyperactivity, and addiction to starvation, exacerbating the dieting and exercising, thus further activating SIRT1. We propose SIRT1 inhibition can break this cycle and provide a potential therapy for individuals suffering from AN.
Highlights
Food consumption is fundamental for life, and eating disorders often result in devastating or life-threatening conditions
We suggest that SIRT1 inhibition results in the upregulation of the transcription factors (TFs) nuclear respiratory factor 1 (NRF1), which induces an upregulation of Grin2a, leading to sufficient NMDA (N-methyl-D-aspartate) receptor (NMDAR) function
When mice are subjected to activity-based anorexia (ABA), they voluntarily induce self-starvation, rapidly lose body weight (Supplementary Fig. 1a, b), become hyperactive (Supplementary Fig. 1c), hypothermic, display loss of estrus, induction of hypothalamic–pituitary–adrenal axis signaling, distortion of circadian rhythm (Supplementary Fig. 1d), suffer from stomach ulceration, and will die if they are not removed from the model conditions
Summary
Food consumption is fundamental for life, and eating disorders often result in devastating or life-threatening conditions. Our results suggest that AN may arise from pathological positive feedback loops: voluntary food restriction activates SIRT1, promoting anxiety, hyperactivity, and addiction to starvation, exacerbating the dieting and exercising, further activating SIRT1. Anorexia nervosa (AN) is characterized by a persistent restriction of food intake, leading to lowered body weight, constant fear of gaining weight, and psychological disturbances of body perception[1]. Starvation, or extreme dieting, NAD+ levels rise due to an increase in both biosynthesis of NAD+ and the oxidation of NADH to NAD+6 This increase leads to the activation of SIRT1, which further represses the transcription of another NAD+ consumer, PARP1, to increase the available NAD+6. Animals that overexpress (OX) SIRT1 are more active in stressful situations[10] These observations are especially intriguing, since hyperactivity, or excessive exercise, is universally observed in individuals suffering from AN. We propose that SIRT1 inhibition with selisistat is a potential therapeutic target for AN
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