ISSN 1662-4009 (Online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 11.4 | DOI: 10.1530/ey.16.11.4

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

Dallner OS, Marinis JM, Lu YH, 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

Laboratory of Molecular Genetics and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.

To read the full abstract: Nature Medicine 2019; 25(3):507-516.

This paper shows that quantitative leptin expression is controlled by redundant cis elements and trans factors that interact with the proximal promoter together with a long noncoding RNA.

Friedman’s research group discovered the adipocyte hormone leptin more than 20 years ago. They identified loss of leptin as the cause of the dysregulated energy homeostasis in the genetically obese ob/ob mouse. The methods used at that time (positional coning) were innovative and led to success. Although that discovery was a major breakthrough in our understanding of the regulation of body weight, many questions remained unanswered. How is leptin regulated in the organism? The fat content of the adipocyte and the number of adipocytes are decisive for circulating leptin levels. But which molecular mechanisms regulate the quantitative expression of leptin? The current study aimed to answer these questions as well as the follow-up question, whether disruption of these regulatory mechanisms leads to obesity.

Once again, innovative methods were used: transgenic luciferase reporter mice to map cis-elements that regulate leptin expression; DNA affinity pulldown experiments; global run-on sequencing to investigate RNA transcription. These approaches revealed that the transcription of a long noncoding RNA can associate with the wild-type leptin promoter to quantitatively regulate expression of the leptin gene. These findings were confirmed in experimental mouse models and data from large-scale human genetic studies by demonstrating that a lack of this long noncoding RNA leads to hypoleptinemia and obesity.

These results represent another breakthrough since they show there is a subtype of human obesity due to relative leptin deficiency which could be treated by leptin therapy. Furthermore, these results suggest that there may exist other factors regulated by the cellular lipid content of the adipocyte which are able to determine cellular leptin expression.