FOSL2 promotes leptin gene expression in human and mouse adipocytes
Christiane D. Wrann, … , Shao-En Ong, Evan D. Rosen
Christiane D. Wrann, … , Shao-En Ong, Evan D. Rosen
Published February 13, 2012
Citation Information: J Clin Invest. 2012;122(3):1010-1021. https://doi.org/10.1172/JCI58431.
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Research Article Metabolism

FOSL2 promotes leptin gene expression in human and mouse adipocytes

Abstract

The adipocyte-derived hormone leptin is a critical regulator of many physiological functions, ranging from satiety to immunity. Surprisingly, very little is known about the transcriptional pathways that regulate adipocyte-specific expression of leptin. Here, we report studies in which we pursued a strategy integrating BAC transgenic reporter mice, reporter assays, and chromatin state mapping to locate an adipocyte-specific cis-element upstream of the leptin (LEP) gene in human fat cells. Quantitative proteomics with affinity enrichment of protein-DNA complexes identified the transcription factor FOS-like antigen 2 (FOSL2) as binding specifically to the identified region, a result that was confirmed by ChIP. Knockdown of FOSL2 in human adipocytes decreased LEP expression, and overexpression of Fosl2 increased Lep expression in mouse adipocytes. Moreover, the elevated LEP expression observed in obesity correlated well with increased FOSL2 levels in mice and humans, and adipocyte-specific genetic deletion of Fosl2 in mice reduced Lep expression. Taken together, these data identify FOSL2 as a critical regulator of leptin expression in adipocytes.

Authors

Christiane D. Wrann, Jun Eguchi, Aline Bozec, Zhao Xu, Tarjei Mikkelsen, Jeffrey Gimble, Heike Nave, Erwin F. Wagner, Shao-En Ong, Evan D. Rosen

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Figure 3

A 1-kb region 4.5 kb upstream of the leptin gene acts as an adipocyte-specific enhancer.

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A 1-kb region 4.5 kb upstream of the leptin gene acts as an adipocyte-sp...
(A) Tiling PCR across 10 kb upstream (UpA–J), the first intron (I1A–K), and the second intron (intron 2) was performed, and the resulting amplicons were cloned into pGL4 with the Lep promoter in the 5′ position. E1, exon 1. (B) Comparison of Lep mRNA expression during adipogenesis in 3T3-L1 and hASCs using Affymetrix arrays. (C) Luciferase activity of tiled reporter constructs in human adipocytes. Data are shown as relative luciferase units (RLU) and expressed as mean ± SEM. *P < 0.05. (D) Comparison of luciferase activity of element UpE in human pre-adipocytes (Pre-ads) and adipocytes (ads). Data are shown as RLU and expressed as mean ± SEM. *P < 0.05. (E) Luciferase activity of different deletion mutants of the enhancer element UpE in human adipocytes. Numbers indicate the length in base pairs. Data are shown as RLU and expressed as mean ± SEM. *P < 0.05.