title: Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice.
abstract: Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l⁺/⁻ mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration. In the hypothalamus of Rpgrip1l⁺/⁻ mice, and in human fibroblasts with hypomorphic mutations in RPGRIP1L, the number of AcIII-positive cilia is diminished, accompanied by impaired convening of the leptin receptor to the vicinity of the cilium, and diminished pStat3 in response to leptin. These findings suggest that RPGRIP1L may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus.
authors.affiliation: Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. Electronic address: gs2172@columbia.edu.
authors.forename: George
authors.initials: G
authors.lastname: Stratigopoulos
authors.affiliation: Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Jayne F
authors.initials: JF
authors.lastname: Martin Carli
authors.affiliation: Divisions of Developmental Medicine and Genetic Medicine, Department of Pediatrics, Seattle Children's Research Institute and University of Washington 1959 NE Pacific St, Seattle, WA 98195, USA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: O'Day
authors.affiliation: Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Liheng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Leduc
authors.affiliation: Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lanzano
authors.affiliation: Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosenbaum
authors.affiliation: Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Dieter
authors.initials: D
authors.lastname: Egli
authors.affiliation: Divisions of Developmental Medicine and Genetic Medicine, Department of Pediatrics, Seattle Children's Research Institute and University of Washington 1959 NE Pacific St, Seattle, WA 98195, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Doherty
authors.affiliation: Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA. Electronic address: rl232@columbia.edu.
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D050154:Adiposity / Q000235:genetics*; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D002478:Cells, Cultured; D002923:Cilia / Q000235:genetics*; D004435:Eating / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus; D007438:Introns; D020738:Leptin / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011110:Polymorphism, Genetic / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D054411:Receptors, Leptin / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D015430:Weight Gain / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C523257:Ftm protein, mouse; D020738:Leptin; D011506:Proteins; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO