title: Hypoxia-inducible factor 3A gene expression and methylation in adipose tissue is related to adipose tissue dysfunction.
abstract: Recently, a genome-wide analysis identified DNA methylation of the HIF3A (hypoxia-inducible factor 3A) as strongest correlate of BMI. Here we tested the hypothesis that HIF3A mRNA expression and CpG-sites methylation in adipose tissue (AT) and genetic variants in HIF3A are related to parameters of AT distribution and function. In paired samples of subcutaneous AT (SAT) and visceral AT (VAT) from 603 individuals, we measured HIF3A mRNA expression and analyzed its correlation with obesity and related traits. In subgroups of individuals, we investigated the effects on HIF3A genetic variants on its AT expression (N = 603) and methylation of CpG-sites (N = 87). HIF3A expression was significantly higher in SAT compared to VAT and correlated with obesity and parameters of AT dysfunction (including CRP and leucocytes count). HIF3A methylation at cg22891070 was significantly higher in VAT compared to SAT and correlated with BMI, abdominal SAT and VAT area. Rs8102595 showed a nominal significant association with AT HIF3A methylation levels as well as with obesity and fat distribution. HIF3A expression and methylation in AT are fat depot specific, related to obesity and AT dysfunction. Our data support the hypothesis that HIF pathways may play an important role in the development of AT dysfunction in obesity.
authors.affiliation: Department of Medicine, Dermatology und Neurology, Department of Endocrinology und Nephrology, University of Leipzig, Leipzig, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Pfeiffer
authors.affiliation: Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Krüger
authors.affiliation: Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Maierhofer
authors.affiliation: Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Böttcher
authors.affiliation: Department of Medicine, Dermatology und Neurology, Department of Endocrinology und Nephrology, University of Leipzig, Leipzig, Germany.|Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.affiliation: Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Nady
authors.initials: N
authors.lastname: El Hajj
authors.affiliation: Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
authors.forename: Dorit
authors.initials: D
authors.lastname: Schleinitz
authors.affiliation: Clinic of Visceral Surgery, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schön
authors.affiliation: Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.|Department of Surgery, University of Leipzig, Leipzig, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Dietrich
authors.affiliation: Department of Medicine, Dermatology und Neurology, Department of Endocrinology und Nephrology, University of Leipzig, Leipzig, Germany.|Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Fasshauer
authors.affiliation: Municipal Clinic Dresden-Neustadt, Dresden, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Lohmann
authors.affiliation: Municipal Clinic Dresden-Neustadt, Dresden, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Dreßler
authors.affiliation: Department of Medicine, Dermatology und Neurology, Department of Endocrinology und Nephrology, University of Leipzig, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.affiliation: Institute of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
authors.affiliation: Department of Medicine, Dermatology und Neurology, Department of Endocrinology und Nephrology, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Leipzig University Medical Center, IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
mesh_terms: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D050218:Body Fat Distribution; D015992:Body Mass Index; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000503:physiopathology*; D012097:Repressor Proteins; D050151:Subcutaneous Fat / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C116973:HIF3A protein, human