title: Human leptin tissue distribution, but not weight loss-dependent change in expression, is associated with methylation of its promoter.
abstract: Leptin is a master regulator of energy homeostasis. Its expression, prevalently localized in adipocytes, is positively related to adipose mass. Epigenetics is emerging as an important contributor to the changes in gene expression undergone by adipose tissue during obesity. We herein investigated the involvement of methylation-dependent mechanisms in leptin regulation in humans. We studied the methylation profile of a 305 bp region in the leptin promoter and analyzed the correspondent leptin expression in visceral adipocyte fraction (AF) and stromal vascular fraction (SVF) of white adipose tissue (WAT) and liver. We found an inverse relationship between methylation and leptin expression with AF displaying a lower methylation density (8%) than SVF and liver (18%, 21%). We evidenced a hot spot region, which mostly differentiates AF versus liver. This includes C15 and 21, which are within the recognition sequences for the transcription factors Sp1 and C/EBP, and C22-23/24, flanking a TATA box. In vitro studies demonstrated that demethylation (by decitabine) increase or de novo activate leptin expression in primary fibroblasts and HeLa cells, respectively. A longitudinal study carried out in patients analyzed before and after bariatric surgery-induced weight loss indicated that in this case decrease in WAT leptin expression (about 50%) does not correspond to changes in promoter methylation density. In conclusion, methylation density in the leptin promoter constitutes one control level for cell type specific leptin expression, whereas weight-loss induced changes in leptin expression does not seem to be methylation-dependent.
authors.affiliation: Dulbecco Telethon Institute; Rome, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Marchi
authors.forename: Simonetta
authors.initials: S
authors.lastname: Lisi
authors.forename: Michele
authors.initials: M
authors.lastname: Curcio
authors.forename: Serena
authors.initials: S
authors.lastname: Barbuti
authors.forename: Paolo
authors.initials: P
authors.lastname: Piaggi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ceccarini
authors.forename: Monica
authors.initials: M
authors.lastname: Nannipieri
authors.forename: Marco
authors.initials: M
authors.lastname: Anselmino
authors.forename: Claudio
authors.initials: C
authors.lastname: Di Salvo
authors.forename: Paolo
authors.initials: P
authors.lastname: Vitti
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinchera
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Santini
authors.forename: Margherita
authors.initials: M
authors.lastname: Maffei
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism; D020738:Leptin / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: D020738:Leptin