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

• Published in: Nature medicine Vol. 25; no. 3; pp. 507 - 516
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2019; Nature Publishing Group
• Subjects: 631/208/176; 631/337/384/2568; 631/443/319/1642/393; 692/163/2743; Animals; Antisense RNA; Biochemistry; Biomedical and Life Sciences; Biomedicine; Body fat; Body weight; Body Weight - drug effects; Body Weight - genetics; Cancer Research; Diet, High-Fat; Eating - drug effects; Eating - genetics; Enhancer Elements, Genetic - genetics; Female; Food intake; Gene expression; Gene Expression Regulation; Genes; Genetic polymorphisms; Health aspects; Humans; Infectious Diseases; Leptin; Leptin - genetics; Leptin - metabolism; Leptin - pharmacology; Male; Medical law; Medical schools; Metabolic Diseases; Mice; Mice, Knockout; Mice, Transgenic; Molecular Medicine; Neurosciences; Obesity; Obesity - genetics; Obesity - metabolism; Polymorphism, Single Nucleotide; Promoters (Genetics); Regulatory mechanisms (biology); Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; Rodents; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Weight loss
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-019-0370-1

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. Defects in the regulation of leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity.