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.

Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers

“…ChIP-seq analysis for C/EBP and AP-1 factors that are abundant in adipocytes revealed significant enrichment at down-regulated eRNAs of both C/EBPa and FOSL2 (Fig. 5B), which has been shown to play a role in adipocyte gene expression (Wrann et al 2012). A higher percentage of downregulated eRNAs, compared with up-regulated and nonregulated, had C/EBPa and FOSL2 bound, and, interestingly, although C/EBPa has been shown to be enriched near genes repressed after rosi treatment (Vernochet et al 2009;Haakonsson et al 2013), the enrichment was The closest known motif, the DR1 motif, is shown for reference.…”

Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia

“…Thus, mice overexpressing Fra-2 develop an osteosclerotic phenotype, whereas the absence of Fra-2 leads to a defect of osteoblast differentiation 15 and a giant osteoclast phenotype induced by the activation of HIF1a. 16 Furthermore, leptin is a transcriptional target of Fra-2, 17 suggesting that Fra-2 may indeed represent an important transcription factor for adipocytes. Herein, we show that Fra-2 deletion in adipocytes affects body and fat pad mass by the regulation of adipocyte number.…”

Osteoblast-specific expression of Fra-2/AP-1 controls Adiponectin/Osteocalcin expression and affects metabolism

“…Distinct target genes are regulated by the Fos-related proteins Fra-1 and Fra-2, which control osteoblast differentiation and activity, rather than osteoblast numbers (Bozec et al, 2010;Eferl et al, 2004). Fra-2 transcriptionally regulates leptin, which can control energy homeostasis in mesenchymal cells (Wrann et al, 2012). Surprisingly, leptin was not affected in Fra-2 mutant mice, whereas the levels of the adipokine Adipoq were found to be altered in Fra-2 mutant sera.…”

“…Fra-2 expression in osteoblasts controls Adipoq production Fra-2 was recently shown to control leptin expression in adipocytes (Wrann et al, 2012). We therefore measured the levels of serum adipokines and Ocn isoforms in Fra-2 mutant mice.…”