近日，來自美國貝勒醫(yī)學院的研究人員在國際學術(shù)期刊cell metabolism在線發(fā)表了一項最新研究進展，他們揭示了哺乳動物生物鐘調(diào)節(jié)脂肪組織與腦之間的leptin內(nèi)分泌反饋回路維持機體長期能量平衡的重要作用，同時還發(fā)現(xiàn)慢性時差改變足以誘導(dǎo)中樞l(wèi)eptin抵抗。
之前有研究表明，時差紊亂與肥胖發(fā)生存在關(guān)聯(lián)，這表明中樞生物鐘在調(diào)節(jié)體重方面可能具有重要作用。
在這項研究中，研究人員利用野生型小鼠和三株生物鐘基因突變小鼠模型進行了篩選，打亂其內(nèi)在生物鐘，結(jié)果發(fā)現(xiàn)生物鐘在維持leptin神經(jīng)內(nèi)分泌反饋回路的長期穩(wěn)定方面具有重要作用。他們發(fā)現(xiàn)在脂肪組織中，BMAL1/CLOCK異二聚體能夠通過調(diào)節(jié)leptin基因的強力轉(zhuǎn)錄共激活因子C/EBPa的活性直接影響leptin的表達，這種調(diào)控作用足以改變血清中l(wèi)eptin水平，使其隨節(jié)律改變。而在中樞神經(jīng)系統(tǒng)中，中樞生物鐘能夠根據(jù)節(jié)律變化激發(fā)ARC神經(jīng)元對循環(huán)系統(tǒng)中l(wèi)eptin的應(yīng)答反應(yīng)。中樞與外周生物鐘的協(xié)同作用可引起一系列與節(jié)律相關(guān)的變化，如進食，活動度，血漿leptin水平，ARC神經(jīng)元中LEPR-B介導(dǎo)的STAT3-POMC信號途徑以及能量消耗水平。
除此之外，研究人員還利用Per和Cry突變小鼠進行研究，也發(fā)現(xiàn)leptin信號途徑會受到節(jié)律的調(diào)節(jié)。
總得來說，這項研究發(fā)現(xiàn)慢性節(jié)律紊亂會干擾內(nèi)源性脂肪組織生物鐘，同時誘導(dǎo)中樞神經(jīng)系統(tǒng)對leptin產(chǎn)生抵抗，這表明leptin抵抗可能在節(jié)律紊亂誘導(dǎo)的肥胖及代謝綜合征中發(fā)揮重要作用。
原文內(nèi)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.