title: Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate.
abstract: Over 1 billion people are estimated to be overweight, placing them at risk for diabetes, cardiovascular disease, and cancer. We performed a systems-level genetic dissection of adiposity regulation using genome-wide RNAi screening in adult Drosophila. As a follow-up, the resulting approximately 500 candidate obesity genes were functionally classified using muscle-, oenocyte-, fat-body-, and neuronal-specific knockdown in vivo and revealed hedgehog signaling as the top-scoring fat-body-specific pathway. To extrapolate these findings into mammals, we generated fat-specific hedgehog-activation mutant mice. Intriguingly, these mice displayed near total loss of white, but not brown, fat compartments. Mechanistically, activation of hedgehog signaling irreversibly blocked differentiation of white adipocytes through direct, coordinate modulation of early adipogenic factors. These findings identify a role for hedgehog signaling in white/brown adipocyte determination and link in vivo RNAi-based scanning of the Drosophila genome to regulation of adipocyte cell fate in mammals.
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Science, Dr. Bohrgasse 3, A 1030 Vienna, Austria.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: Daniel
authors.initials: D
authors.lastname: Schramek
authors.forename: Harald
authors.initials: H
authors.lastname: Schnidar
authors.forename: Shane J F
authors.initials: SJ
authors.lastname: Cronin
authors.forename: Nadine T
authors.initials: NT
authors.lastname: Nehme
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhang
authors.forename: Claude
authors.initials: C
authors.lastname: Knauf
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Karin
authors.initials: K
authors.lastname: Aumayr
authors.forename: Jelena
authors.initials: J
authors.lastname: Todoric
authors.forename: Martina
authors.initials: M
authors.lastname: Bayer
authors.forename: Arvand
authors.initials: A
authors.lastname: Haschemi
authors.forename: Vijitha
authors.initials: V
authors.lastname: Puviindran
authors.forename: Krisztina
authors.initials: K
authors.lastname: Tar
authors.forename: Michael
authors.initials: M
authors.lastname: Orthofer
authors.forename: G Gregory
authors.initials: GG
authors.lastname: Neely
authors.forename: Georg
authors.initials: G
authors.lastname: Dietzl
authors.forename: Armen
authors.initials: A
authors.lastname: Manoukian
authors.forename: Martin
authors.initials: M
authors.lastname: Funovics
authors.forename: Gerhard
authors.initials: G
authors.lastname: Prager
authors.forename: Oswald
authors.initials: O
authors.lastname: Wagner
authors.forename: Dominique
authors.initials: D
authors.lastname: Ferrandon
authors.forename: Fritz
authors.initials: F
authors.lastname: Aberger
authors.forename: Chi-chung
authors.initials: CC
authors.lastname: Hui
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism; D052438:Adipocytes, White / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000378:metabolism; D009765:Obesity / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D005938:Glucocorticoids; D053823:Hedgehog Proteins; D012097:Repressor Proteins; C490763:Sufu protein, mouse; C077245:hh protein, Drosophila; D000242:Cyclic AMP