New insights into adipocyte-specific leptin gene expression

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. In a recent published study, we pursued a strategy integrating BAC transgenic reporter mice, in vitro reporter assays, and chromatin state mapping to locate an adipocyte-specific cis-element upstream of the LEP gene in human fat cells. Quantitative proteomics (stable isotope labeling by amino acids in cell culture, SILAC) with affinity enrichment of protein-DNA complexes identified the transcription factor FOSL2 as a specific binder to the identified region. We confirmed that FOSL2 is an important regulator of LEP gene expression in vitro and in vivo using cell culture models and genetic mouse models. In this commentary, we discuss the transcriptional regulation of LEP gene expression, our strategy to identify an adipocyte-specific cis-regulatory element and the transcription factor(s) responsible for LEP gene expression. We also discuss our data on FOSL2 and leptin levels in physiology and pathophysiology. We speculate on unanswered questions and future directions.

Maternal obesity programs increased leptin gene expression in rat male offspring via epigenetic modifications in a depot-specific manner

“…Several studies support this notion for leptin gene expression [25], [29], [30], [31], [32], [33], [34]. In line with these findings, the epigenome of intergenic regions was more affected than promoter regions in offspring of perinatally malnourished dams [38].…”

Leptin and brain–adipose crosstalks

“…In addition, the Lep promoter contains functional binding sites for CCAAT/enhancer-binding proteins (CEBPs), the transcription factor SP1, the glucocorticoid receptor (GR), cAMP-responsive element-binding protein (CREB) and sterol regulatory element-binding protein 1C (SREBP1C) 65–71 . These transcription factors are unlikely to mediate the SNS-dependent regulation of Lep expression, however, as they do not seem to mediate the effects of fasting or feeding on leptin levels 72 . Moreover, the potential transcription factors repressing leptin in response to cold are still unknown.…”

Satietogenic Protein from Tamarind Seeds Decreases Food Intake, Leptin Plasma and <b><i>CCK-1r</i></b> Gene Expression in Obese Wistar Rats

“…A study evaluating the sensitivity of obese animals to peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) found plasma reductions of these hormones, which was not corroborated by gene expression [52]. Concerning leptin, little is known about the transcription pathways that regulate its specific expression in adipocytes [53]. …”