Autophagy failure is associated with metabolic insufficiency. Although caloric restriction (CR) extends healthspan, its adherence in humans is poor. We established an isocaloric twice-a-day (ITAD) feeding model wherein ITAD-fed mice consume the same food amount asad libitumcontrols but at two short windows early and late in the diurnal cycle. We hypothesized that ITAD feeding will provide two intervals of intermeal fasting per circadian period and induce autophagy. We show that ITAD feeding modifies circadian autophagy and glucose/lipid metabolism that correlate with feeding-driven changes in circulating insulin. ITAD feeding decreases adiposity and, unlike CR, enhances muscle mass. ITAD feeding drives energy expenditure, lowers lipid levels, suppresses gluconeogenesis, and prevents age/obesity-associated metabolic defects. Using liver-, adipose-, myogenic-, and proopiomelanocortin neuron-specific autophagy-null mice, we mapped the contribution of tissue-specific autophagy to system-wide benefits of ITAD feeding. Our studies suggest that consuming two meals a day without CR could prevent the metabolic syndrome.

中文翻译：

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自噬对全麦空腹的全系统益处

自噬失败与代谢功能不全相关。尽管热量限制（CR）可以延长健康期，但其在人体中的依从性却很差。我们建立了每天两次的等温喂养（ITAD）喂养模型，其中由ITAD喂养的小鼠消耗的食物量与自由对照组相同，但在昼夜周期的早晚两个短窗口内。我们假设ITAD喂养将在每个昼夜节律间隔提供两次间隔的空腹进食并诱导自噬。我们表明，ITAD喂养可以改变昼夜节律自噬和葡萄糖/脂质代谢，这与喂养驱动的循环胰岛素变化相关。与CR不同，ITAD喂养可减少肥胖，并增加肌肉质量。ITAD喂养可增加能量消耗，降低脂质水平，抑制糖异生，并防止与年龄/肥胖相关的代谢缺陷。使用肝脏，脂肪 对于肌原性和proopiomelanocortin神经元特异性自噬无效小鼠，我们绘制了组织特异性自噬对ITAD喂养全系统益处的贡献。我们的研究表明，一天不吃CR的两餐可以预防代谢综合征。