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

Olof S Dallner; Jill M Marinis; Yi-Hsueh Lu; Kivanc Birsoy; Emory Werner; Gulya Fayzikhodjaeva; Brian D Dill; Henrik Molina; Arden Moscati; Zoltán Kutalik; Pedro Marques-Vidal; Tuomas O Kilpeläinen; Niels Grarup; Allan Linneberg; Yinxin Zhang; Roger Vaughan; Ruth J F Loos; Mitchell A Lazar; Jeffrey M Friedman

doi:10.1038/s41591-019-0370-1

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

Olof S Dallner, Jill M Marinis, Yi-Hsueh Lu, Kivanc Birsoy, Emory Werner, Gulya Fayzikhodjaeva, Brian D Dill, Henrik Molina, Arden Moscati, Zoltán Kutalik, Pedro Marques-Vidal, Tuomas O Kilpeläinen, Niels Grarup, Allan Linneberg, Yinxin Zhang, Roger Vaughan, Ruth J F Loos, Mitchell A Lazar, Jeffrey M Friedman

84 Citations (Scopus)

Abstract

Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.

Original language	English
Journal	Nature Medicine
Volume	25
Issue number	3
Pages (from-to)	507-516
Number of pages	10
ISSN	1078-8956
DOIs	https://doi.org/10.1038/s41591-019-0370-1
Publication status	Published - Mar 2019

Access to Document

10.1038/s41591-019-0370-1

Cite this

Dallner, O. S., Marinis, J. M., Lu, Y.-H., Birsoy, K., Werner, E., Fayzikhodjaeva, G., Dill, B. D., Molina, H., Moscati, A., Kutalik, Z., Marques-Vidal, P., Kilpeläinen, T. O., Grarup, N., Linneberg, A., Zhang, Y., Vaughan, R., Loos, R. J. F., Lazar, M. A., & Friedman, J. M. (2019). Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity. Nature Medicine, 25(3), 507-516. https://doi.org/10.1038/s41591-019-0370-1

Dallner, OS, Marinis, JM, Lu, Y-H, Birsoy, K, Werner, E, Fayzikhodjaeva, G, Dill, BD, Molina, H, Moscati, A, Kutalik, Z, Marques-Vidal, P, Kilpeläinen, TO, Grarup, N, Linneberg, A, Zhang, Y, Vaughan, R, Loos, RJF, Lazar, MA & Friedman, JM 2019, 'Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity', Nature Medicine, vol. 25, no. 3, pp. 507-516. https://doi.org/10.1038/s41591-019-0370-1

@article{33992f3330a545db94d4c89ebfa55f27,

title = "Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity",

abstract = "Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.",

author = "Dallner, {Olof S} and Marinis, {Jill M} and Yi-Hsueh Lu and Kivanc Birsoy and Emory Werner and Gulya Fayzikhodjaeva and Dill, {Brian D} and Henrik Molina and Arden Moscati and Zolt{\'a}n Kutalik and Pedro Marques-Vidal and Kilpel{\"a}inen, {Tuomas O} and Niels Grarup and Allan Linneberg and Yinxin Zhang and Roger Vaughan and Loos, {Ruth J F} and Lazar, {Mitchell A} and Friedman, {Jeffrey M}",

year = "2019",

month = mar,

doi = "10.1038/s41591-019-0370-1",

language = "English",

volume = "25",

pages = "507--516",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "3",

}

TY - JOUR

T1 - Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity

AU - Dallner, Olof S

AU - Marinis, Jill M

AU - Lu, Yi-Hsueh

AU - Birsoy, Kivanc

AU - Werner, Emory

AU - Fayzikhodjaeva, Gulya

AU - Dill, Brian D

AU - Molina, Henrik

AU - Moscati, Arden

AU - Kutalik, Zoltán

AU - Marques-Vidal, Pedro

AU - Kilpeläinen, Tuomas O

AU - Grarup, Niels

AU - Linneberg, Allan

AU - Zhang, Yinxin

AU - Vaughan, Roger

AU - Loos, Ruth J F

AU - Lazar, Mitchell A

AU - Friedman, Jeffrey M

PY - 2019/3

Y1 - 2019/3

N2 - Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.

AB - Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.

U2 - 10.1038/s41591-019-0370-1

DO - 10.1038/s41591-019-0370-1

M3 - Journal article

C2 - 30842678

SN - 1078-8956

VL - 25

SP - 507

EP - 516

JO - Nature Medicine

JF - Nature Medicine

IS - 3

ER -

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

Abstract

Access to Document

Fingerprint

Cite this