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

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  • 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
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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 languageEnglish
JournalNature Medicine
Volume25
Issue number3
Pages (from-to)507-516
Number of pages10
ISSN1078-8956
DOIs
Publication statusPublished - Mar 2019

ID: 56779597