Nature Medicine //瘦素相关的长链非编码RNA失去管制将导致瘦素效应式肥胖

Dysregulation of a longnoncoding RNA reduces leptin leading to a leptin-responsive form of obesity

Olof S. Dallner¹, Jill M. Marinis², Yi-Hsueh. Lu¹,Kivanc Birsoy ³, Emory Werner¹, GulyaFayzikhodjaeva1,Brian D. Dill ⁴, Henrik Molina⁴, ArdenMoscati⁵, Zoltán Kutalik^6,7, Pedro Marques-Vidal ⁸,TuomasO. Kilpeläinen⁹, Niels Grarup ⁹, Allan Linneberg ^10,11,12,Yinxin Zhang ¹, Roger Vaughan¹³, Ruth J. F. Loos^5,14,Mitchell A. Lazar² and Jeffrey M. Friedman ^1,15

Nature Medicine. 18 January 2019.（IF 2018 = 30.641）

[doi: 10.1038/s41591-019-0370-1.]

Abstract

Leptin is an adipocyte hormone that functions as an afferent signal in anegative feedback loop that maintains homeostatic control of adipose tissuemass. Leptin is expressed exclusivelyin adipocytes and is quantitatively regulated such thatchanges in fat mass correlate with changes in expression of the leptin gene(Lep). Complete leptin deficiency in humans can be caused by rare mutations inthe leptin gene but accounts for only a few dozen cases of obesity. A fullerunderstanding of the mechanism controlling leptin expression could be ofclinical importance, as transgenic mice expressing constitutively low leptinlevels show increases in food intake and body weight and patients who areheterozygous for mutations in the leptin gene show increased weight. Inaddi-tion, a substantial subset of obese patients have relatively low cir-culatinglevels of leptin. In principle, alterations in transcriptional control of theendogenous leptin gene could potentially lead to obesity by reducing the amountof leptin that is produced from fat cells. However, none of the factors thatquantitatively regulate this gene have been identified and the possibility thatdefects in this sys-tem could cause obesity has not been established.This is of par-ticular importance because it is possible thatobese patients with low leptin levels remain leptin sensitive and might loseweight onleptin therapy.Here we report that a fat-specific long noncoding RNA (lncRNA) that isregulated in concert with fat mass interacts with redundant enhancers toregulate qualitative and quantitative expression of the leptin gene and thatdefects in this system lead to relative hypoleptinemia and a leptin-responsiveform of obesity. In addition, association analyses in large-scale human geneticstudies support a role for lncOb in regulating leptin expression in humans.

推荐理由：

瘦素浓度的定量变化导致食物摄入量和体重的变化，但控制瘦素基因表达的调节机制尚不清楚。在这里，作者报道了脂肪特异性以及瘦素的定量表达是由多种顺式元件及反式作用因子与长链非编码RNA（lncOb）共同作用于瘦素基因的近端启动子来控制的。饮食诱导肥胖敲除lncOb小鼠表现出增加的脂肪量以及减少的血浆瘦素水平，瘦素治疗后肥胖小鼠体重减轻，而对照小鼠的体重则没有减轻。和这发现一致的是，对人类进行的大规模遗传研究进行分析发现，人类的lncOb基因区域的单核苷酸多态性（SNPs）与较低的血浆瘦素水平和肥胖显著相关。这篇文章有趣，思路和方法值得借鉴和学习