近日，来自美国贝勒医学院的研究人员在国际学术期刊cell metabolism在线发表了一项最新研究进展，他们揭示了哺乳动物生物钟调节脂肪组织与脑之间的leptin内分泌反馈回路维持机体长期能量平衡的重要作用，同时还发现慢性时差改变足以诱导中枢leptin抵抗。
之前有研究表明，时差紊乱与肥胖发生存在关联，这表明中枢生物钟在调节体重方面可能具有重要作用。
在这项研究中，研究人员利用野生型小鼠和三株生物钟基因突变小鼠模型进行了筛选，打乱其内在生物钟，结果发现生物钟在维持leptin神经内分泌反馈回路的长期稳定方面具有重要作用。他们发现在脂肪组织中，BMAL1/CLOCK异二聚体能够通过调节leptin基因的强力转录共激活因子C/EBPa的活性直接影响leptin的表达，这种调控作用足以改变血清中leptin水平，使其随节律改变。而在中枢神经系统中，中枢生物钟能够根据节律变化激发ARC神经元对循环系统中leptin的应答反应。中枢与外周生物钟的协同作用可引起一系列与节律相关的变化，如进食，活动度，血浆leptin水平，ARC神经元中LEPR-B介导的STAT3-POMC信号途径以及能量消耗水平。
除此之外，研究人员还利用Per和Cry突变小鼠进行研究，也发现leptin信号途径会受到节律的调节。
总得来说，这项研究发现慢性节律紊乱会干扰内源性脂肪组织生物钟，同时诱导中枢神经系统对leptin产生抵抗，这表明leptin抵抗可能在节律紊乱诱导的肥胖及代谢综合征中发挥重要作用。
原文内容：Circadian Dysfunction Induces Leptin Resistance in Mice
Nicole M. Kettner, Sara A. Mayo, Jack Hua, Choogon Lee, David D. Moorecorrespondenceemail, Loning Fu
Circadian disruption is associated with obesity, implicating the central clock in body weight control. Our comprehensive screen of wild-type and three circadian mutant mouse models, with or without chronic jet lag, shows that distinct genetic and physiologic interventions differentially disrupt overall energy homeostasis and Leptin signaling. We found that BMAL1/CLOCK generates circadian rhythm of C/EBPα-mediated leptin transcription in adipose. Per and Crymutant mice show similar disruption of peripheral clock and deregulation of leptin in fat, but opposite body weight and composition phenotypes that correlate with their distinct patterns of POMC neuron deregulation in the arcuate nucleus. Chronic jet lag is sufficient to disrupt the endogenous adipose clock and also induce central Leptin resistance in wild-type mice. Thus, coupling of the central and peripheral clocks controls Leptin endocrine feedback homeostasis. We propose that Leptin resistance, a hallmark of obesity in humans, plays a key role in circadian dysfunction-induced obesity and metabolic syndromes.