Circadian intervention of obesity development via resting-stage feeding manipulation or oxytocin treatment.
Circadian intervention of obesity development via resting-stage feeding manipulation or oxytocin treatment.
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DOI：
10.1152/ajpendo.00196.2011
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发表时间：
2011-11
期刊：
影响因子：
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通讯作者：
Guo Zhang;D. Cai
中科院分区：
文献类型：
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作者：
Guo Zhang;D. Cai
肥胖大流行可以被视为对不断变化的环境因素做出不平衡反应的结果。最近的研究已经将昼夜节律与肥胖和相关疾病联系起来；然而，潜在的机制仍然不清楚。在这项研究中，我们发现，高脂饮食(HFD)喂养显著促进了小鼠白天的卡路里摄入量，而不是夜间的卡路里摄入量，导致了饮食的昼夜节律性。使用规定的每日HFD摄入量的计划喂养，我们发现，白天和夜间喂养比例的增加会促进体重增加，而这一比例的降低则会重新平衡能量消耗，以抵消肥胖。在确定其可能的机制时，我们发现下丘脑分泌的厌食性神经肽催产素呈现昼夜节律上升和下降的节律，这种节律与正常饮食小鼠的日常摄食活动呈负相关。相反，慢性高脂饮食可抑制催产素的昼夜节律性，主要是通过抑制日间催产素的升高。通过下丘脑注射催产素或催产素拮抗剂的药理学实验，我们表明，白天操作催产素可以改变摄食昼夜节律模式，重新规划能量消耗，导致肥胖的减轻或诱导，而不依赖于24小时的卡路里摄入量。同样重要的是，我们发现外周注射催产素能激活下丘脑催产素神经元释放催产素，并发挥类似于中枢催产素注射的代谢效应，从而为应用催产素控制肥胖提供了一条实用的临床途径。总之，静息期催产素的释放和摄食活动是肥胖的关键生理机制和治疗目标。
The obesity pandemic can be viewed as a result of an imbalanced reaction to changing environmental factors. Recent research has linked circadian arrhythmicity to obesity and related diseases; however, the underlying mechanisms are still unclear. In this study, we found that high-fat diet (HFD) feeding strikingly promoted daytime rather than nighttime caloric intake in mice, leading to feeding circadian arrhythmicity. Using scheduled feeding with a defined amount of daily HFD intake, we found that an increase in the ratio of daytime to nighttime feeding promoted weight gain, whereas a decrease of this ratio rebalanced energy expenditure to counteract obesity. In identifying the underlying mechanism, we found that hypothalamic release of anorexigenic neuropeptide oxytocin displayed a diurnal rhythm of daytime rise and nighttime decline, which negatively correlated with the diurnal feeding activities of normal chow-fed mice. In contrast, chronic HFD feeding abrogated oxytocin diurnal rhythmicity, primarily by suppressing daytime oxytocin rise. Using pharmacological experiments with hypothalamic injection of oxytocin or oxytocin antagonist, we showed that daytime manipulation of oxytocin can change feeding circadian patterns to reprogram energy expenditure, leading to attenuation or induction of obesity independently of 24-h caloric intake. Also importantly, we found that peripheral injection of oxytocin activated hypothalamic oxytocin neurons to release oxytocin, and exerted metabolic effects similar to central oxytocin injection, thus offering a practical clinical avenue to use oxytocin in obesity control. In conclusion, resting-stage oxytocin release and feeding activity represent a critical circadian mechanism and therapeutic target for obesity.