A noncanonical PPAR gamma/RXR alpha-binding sequence regulates leptin expression in response to changes in adipose tissue mass

作者：Zhang Yinxin; Danner Olof Stefan; Nakadai Tomoyoshi; Fayzikhodjaeva Gulya; Lu Yi Hsueh; Lazar Mitchell A; Roeder Robert G; Friedman Jeffrey M^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2018, 115(26): E6039-E6047.

DOI：10.1073/pnas.1806366115

• leptin
• adipose tissue
• PPAR gamma/RXR alpha
• weak binding
• lipid sensing

Leptin expression decreases after fat loss and is increased when obesity develops, and its proper quantitative regulation is essential for the homeostatic control of fat mass. We previously reported that a distant leptin enhancer 1 (LE1), 16 kb upstream from the transcription start site (TSS), confers fat-specific expression in a bacterial artificial chromosome transgenic (BACTG) reporter mouse. However, this and the other elements that we identified do not account for the quantitative changes in leptin expression that accompany alterations of adipose mass. In this report, we used an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to identify a 17-bp noncanonical peroxisome proliferator-activated receptor gamma (PPAR gamma)/retinoid X receptor alpha (RXR alpha)-binding site, leptin regulatory element 1 (LepRE1), within LE1, and show that it is necessary for the fat-regulated quantitative control of reporter (luciferase) expression. While BACTG reporter mice with mutations in this sequence still show fat-specific expression, luciferase is no longer decreased after food restriction and weight loss. Similarly, the increased expression of leptin reporter associated with obesity in oWob mice is impaired. A functionally analogous LepRE1 site is also found in a second, redundant DNA regulatory element 13 kb downstream of the TSS. These data uncouple the mechanisms conferring qualitative and quantitative expression of the leptin gene and further suggest that factor(s) that bind to LepRE1 quantitatively control leptin expression and might be components of a lipid-sensing system in adipocytes.

• 出版日期2018-6-26