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. Kilpel?inen⁹, 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.

推薦理由：

瘦素濃度的定量變化導(dǎo)致食物攝入量和體重的變化，但控制瘦素基因表達的調(diào)節(jié)機制尚不清楚。在這里，作者報道了脂肪特異性以及瘦素的定量表達是由多種順式元件及反式作用因子與長鏈非編碼RNA（lncOb）共同作用于瘦素基因的近端啟動子來控制的。飲食誘導(dǎo)肥胖敲除lncOb小鼠表現(xiàn)出增加的脂肪量以及減少的血漿瘦素水平，瘦素治療后肥胖小鼠體重減輕，而對照小鼠的體重則沒有減輕。和這發(fā)現(xiàn)一致的是，對人類進行的大規(guī)模遺傳研究進行分析發(fā)現(xiàn)，人類的lncOb基因區(qū)域的單核苷酸多態(tài)性（SNPs）與較低的血漿瘦素水平和肥胖顯著相關(guān)。這篇文章有趣，思路和方法值得借鑒和學(xué)習(xí)