FOSL2 promotes leptin gene expression in human and mouse adipocytes.
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.
Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Christiane D
CD
Wrann
Jun
J
Eguchi
Aline
A
Bozec
Zhao
Z
Xu
Tarjei
T
Mikkelsen
Jeffrey
J
Gimble
Heike
H
Nave
Erwin F
EF
Wagner
Shao-En
SE
Ong
Evan D
ED
Rosen
D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation; D002843:Chromatin / Q000737:chemistry; D002874:Chromosome Mapping; D005260:Female; D051921:Fos-Related Antigen-2 / Q000378:metabolism*; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D023281:Genomics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D020738:Leptin / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D040901:Proteomics / Q000379:methods
D002843:Chromatin; C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; D020738:Leptin; D049452:Green Fluorescent Proteins