title: Hypomorphism of Fto and Rpgrip1l causes obesity in mice.
abstract: Noncoding polymorphisms in the fat mass and obesity-associated (FTO) gene represent common alleles that are strongly associated with effects on food intake and adiposity in humans. Previous studies have suggested that the obesity-risk allele rs8050136 in the first intron of FTO alters a regulatory element recognized by the transcription factor CUX1, thereby leading to decreased expression of FTO and retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Here, we evaluated the effects of rs8050136 and another potential CUX1 element in rs1421085 on expression of nearby genes in human induced pluripotent stem cell-derived (iPSC-derived) neurons. There were allele-dosage effects on FTO, RPGRIP1L, and AKT-interacting protein (AKTIP) expression, but expression of other vicinal genes, including IRX3, IRX5, and RBL2, which have been implicated in mediating functional effects, was not altered. In vivo manipulation of CUX1, Fto, and/or Rpgrip1l expression in mice affected adiposity in a manner that was consistent with CUX1 influence on adiposity via remote effects on Fto and Rpgrip1l expression. In support of a mechanism, mice hypomorphic for Rpgrip1l exhibited hyperphagic obesity, as the result of diminished leptin sensitivity in Leprb-expressing neurons. Together, the results of this study indicate that the effects of FTO-associated SNPs on energy homeostasis are due in part to the effects of these genetic variations on hypothalamic FTO, RPGRIP1L, and possibly other genes.
authors.forename: George
authors.initials: G
authors.lastname: Stratigopoulos
authors.forename: Lisa Cole
authors.initials: LC
authors.lastname: Burnett
authors.forename: Richard
authors.initials: R
authors.lastname: Rausch
authors.forename: Richard
authors.initials: R
authors.lastname: Gill
authors.forename: David Barth
authors.initials: DB
authors.lastname: Penn
authors.forename: Alicja A
authors.initials: AA
authors.lastname: Skowronski
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Lanzano
authors.forename: Pumin
authors.initials: P
authors.lastname: Zhang
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Storm
authors.forename: Dieter
authors.initials: D
authors.lastname: Egli
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
mesh_terms: D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003598:Cytoskeletal Proteins; D004734:Energy Metabolism / Q000235:genetics; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D007438:Introns; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; C501599:Irx3 protein, mouse; C501601:Irx5 protein, mouse; D011506:Proteins; C493838:Rbl2 protein, mouse; D050717:Retinoblastoma-Like Protein p130; C540216:Rpgrip1 protein, mouse; D014157:Transcription Factors; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO