title: FTO deficiency induces UCP-1 expression and mitochondrial uncoupling in adipocytes.
abstract: Variants in the fat mass- and obesity-associated (FTO) gene are associated with obesity and body fat mass in genome-wide association studies. However, the mechanism by which FTO predisposes individuals to obesity is not clear so far. First mechanistic evidence was shown in Fto-negative mice. These mice are resistant to obesity due to enhanced energy expenditure, whereas the mass of brown adipose tissue remains unchanged. We hypothesize that FTO is involved in the induction of white adipose tissue browning, which leads to mitochondrial uncoupling and increases energy expenditure. Uncoupling protein 1 (Ucp-1) was significantly higher expressed in both gonadal and inguinal adipose depots of Fto(-/-) compared with Fto(+/+) littermates accompanied by the appearance of multivacuolar, Ucp-1-positive adipocytes in these tissues. By using lentiviral short hairpin RNA constructs, we established FTO-deficient human preadipocytes and adipocytes and analyzed key metabolic processes. FTO-deficient adipocytes showed an adipogenic differentiation rate comparable with control cells but exhibited a reduced de novo lipogenesis despite unchanged glucose uptake. In agreement with the mouse data, FTO-deficient adipocytes exhibited 4-fold higher expression of UCP-1 in mitochondria compared with control cells. The up-regulation of UCP-1 in FTO-deficient adipocytes resulted in enhanced mitochondrial uncoupling. We conclude that FTO deficiency leads to the induction of a brown adipocyte phenotype, thereby enhancing energy expenditure. Further understanding of the signaling pathway connecting FTO with UCP-1 expression might lead to new options for obesity and overweight treatment.
authors.affiliation: Division of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Eythstrasse 24, 89075 Ulm, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Tews
authors.forename: P
authors.initials: P
authors.lastname: Fischer-Posovszky
authors.forename: T
authors.initials: T
authors.lastname: Fromme
authors.forename: M
authors.initials: M
authors.lastname: Klingenspor
authors.forename: J
authors.initials: J
authors.lastname: Fischer
authors.forename: U
authors.initials: U
authors.lastname: Rüther
authors.forename: R
authors.initials: R
authors.lastname: Marienfeld
authors.forename: T F
authors.initials: TF
authors.lastname: Barth
authors.forename: P
authors.initials: P
authors.lastname: Möller
authors.forename: K M
authors.initials: KM
authors.lastname: Debatin
authors.forename: M
authors.initials: M
authors.lastname: Wabitsch
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism*; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000378:metabolism; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D050151:Subcutaneous Fat / Q000166:cytology / Q000378:metabolism; D050507:Subcutaneous Fat, Abdominal / Q000166:cytology / Q000378:metabolism; D000071256:Uncoupling Protein 1; D015854:Up-Regulation; D014617:Vacuoles / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011506:Proteins; D034741:RNA, Small Interfering; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human