title: Impaired Mitochondrial Biogenesis in Adipose Tissue in Acquired Obesity.
abstract: Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8-36.2 years of age, who were discordant (ΔBMI >3 kg/m(2), mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (ΔBMI <3 kg/m(2), n = 14) for body weight, and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways with concomitant downregulation of mtDNA amount, mtDNA-dependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways, and OXPHOS proteins in SAT are downregulated in acquired obesity, and are associated with metabolic disturbances already at the preclinical stage.
authors.affiliation: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Sini
authors.identifier: http://orcid.org/0000-0026-3420-0577
authors.initials: S
authors.lastname: Heinonen
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Jana
authors.initials: J
authors.lastname: Buzkova
authors.affiliation: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors.forename: Maheswary
authors.initials: M
authors.lastname: Muniandy
authors.affiliation: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland Siluetti Hospital, Helsinki, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Kaksonen
authors.affiliation: Department of Public Health, University of Helsinki, Helsinki, Finland.
authors.forename: Miina
authors.identifier: http://orcid.org/0000-0003-3661-7400
authors.initials: M
authors.lastname: Ollikainen
authors.affiliation: Department of Public Health, University of Helsinki, Helsinki, Finland.
authors.forename: Khadeeja
authors.initials: K
authors.lastname: Ismail
authors.affiliation: Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Hakkarainen
authors.affiliation: Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Jesse
authors.initials: J
authors.lastname: Lundbom
authors.affiliation: Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Lundbom
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
authors.forename: Katriina
authors.initials: K
authors.lastname: Vuolteenaho
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland.
authors.forename: Eeva
authors.initials: E
authors.lastname: Moilanen
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland Finnish Twin Cohort Study, Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.affiliation: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Aila
authors.initials: A
authors.lastname: Rissanen
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
authors.affiliation: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland Abdominal Center, Endocrinology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland kirsi.pietilainen@helsinki.fi.
authors.forename: Kirsi H
authors.initials: KH
authors.lastname: Pietiläinen
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002952:Citric Acid Cycle / Q000235:genetics; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance / Q000235:genetics; D007657:Ketone Bodies / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000235:genetics*; D009765:Obesity / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D010085:Oxidative Phosphorylation; D050151:Subcutaneous Fat / Q000276:immunology / Q000378:metabolism*; D014430:Twins, Monozygotic
chemical_list: D016207:Cytokines; D004272:DNA, Mitochondrial; D005227:Fatty Acids; D007657:Ketone Bodies