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Nat Med. 2019 Mar;25(3):507-516. doi: 10.1038/s41591-019-0370-1. Epub 2019 Mar 6.

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

Author information

1
Laboratory of Molecular Genetics, The Rockefeller University, New York, NY, USA.
2
Division of Endocrinology, Diabetes, and Metabolism and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
3
Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA.
4
Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
5
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
Institute of Social and Preventive Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
7
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
8
Department of Medicine, Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
9
Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
10
Centre for Clinical Research and Prevention, Frederiksberg-Bispebjerg Hospital, Copenhagen, Denmark.
11
Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.
12
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
13
Department of Biostatistics, The Rockefeller University, New York, NY, USA.
14
The Mindich Childhood and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15
Laboratory of Molecular Genetics, The Rockefeller University, New York, NY, USA. friedj@rockefeller.edu.
16
Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA. friedj@rockefeller.edu.

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.

PMID:
30842678
DOI:
10.1038/s41591-019-0370-1
[Indexed for MEDLINE]

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