Regulatory Modules of Human Thermogenic Adipocytes: Functional Genomics of Meta-Analyses Derived Marker-Genes

Abstract

Recently, ProFAT and BATLAS scores have been offered to determine thermogenic status of adipocytes using expression pattern of brown and white marker-genes. In this work, we investigated the functional context of these genes. Although the two meta-analyses based marker-gene lists have little overlap, their enriched pathways show strong coincides suggesting they may better characterize adipocytes. We demonstrate that functional genomics of the annotated genes in common pathways enables an extended analysis of thermogenesis regulation, generates testable hypotheses supported by experimental results in human adipocytes with different browning potential and may lead to more global conclusions than single-state studies. Our results imply that different biological processes shape brown and white adipocytes with presumed transitional states. We propose that the thermogenic adipocyte phenotype require both repression of whitening and induction of browning. These simultaneous actions and hitherto unnoticed regulatory modules, such as the exemplified HIF1A that may directly act at UCP1 promoter, can set new direction in obesity research. HighlightsO_LIIntegrated pathways better characterize brown adipocytes than marker-genes C_LIO_LIDifferent processes shape the brown and white adipocyte phenotypes C_LIO_LIThermogenic phenotype may require simultaneous repression of whitening and induction of browning C_LIO_LIProtein network analyses reveals unnoticed regulatory modules of adipocyte phenotype C_LIO_LIHIF1A may regulate thermogenesis by direct control of UCP1 gene-expression C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/428057v2_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@b4c730org.highwire.dtl.DTLVardef@813b58org.highwire.dtl.DTLVardef@5f3398org.highwire.dtl.DTLVardef@344eb5_HPS_FORMAT_FIGEXP M_FIG C_FIG