Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
Department of Biomedical Sciences, Cornell University, Ithaca, NY, 14853, USA.
Nat Commun. 2020 Jun 4;11(1):2814. doi: 10.1038/s41467-020-16348-9.
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.
进食是生命的基础，而饮食失调常常导致严重或危及生命的状况。神经性厌食症（AN）的特征是持续限制能量摄入，导致体重下降、持续害怕体重增加以及身体感知的心理障碍。在这里，我们证明 SIRT1 的抑制，无论是通过遗传还是药理学，都可以延迟活动性厌食症（ABA）模型中 AN 行为的发作和进展，而 SIRT1 的激活则加速 ABA 表型。从机制上讲，我们认为 SIRT1 通过与 NRF1 的相互作用促进 ABA 的进展，导致 NMDA 受体亚基 Grin2A 的抑制。我们的结果表明，AN 可能源于病理性正反馈循环：自愿节食会激活 SIRT1，从而引发焦虑、过度活跃和对饥饿的成瘾，加剧节食和运动，从而进一步激活 SIRT1。我们提出 SIRT1 抑制可以打破这种循环，并为患有 AN 的个体提供一种潜在的治疗方法。
