Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity. / Dallner, Olof S; Marinis, Jill M; Lu, Yi-Hsueh; Birsoy, Kivanc; Werner, Emory; Fayzikhodjaeva, Gulya; Dill, Brian D; Molina, Henrik; Moscati, Arden; Kutalik, Zoltán; Marques-Vidal, Pedro; Kilpeläinen, Tuomas O; Grarup, Niels; Linneberg, Allan; Zhang, Yinxin; Vaughan, Roger; Loos, Ruth J F; Lazar, Mitchell A; Friedman, Jeffrey M.
I: Nature Medicine, Bind 25, Nr. 3, 2019, s. 507-530.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2019
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
VL - 25
SP - 507
EP - 530
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 3
ER -
ID: 214691683