Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate.
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.
Pospisilik
J Andrew
JA
Institute of Molecular Biotechnology of the Austrian Academy of Science, Dr. Bohrgasse 3, A 1030 Vienna, Austria.
Schramek
Daniel
D
Schnidar
Harald
H
Cronin
Shane J F
SJ
Nehme
Nadine T
NT
Zhang
Xiaoyun
X
Knauf
Claude
C
Cani
Patrice D
PD
Aumayr
Karin
K
Todoric
Jelena
J
Bayer
Martina
M
Haschemi
Arvand
A
Puviindran
Vijitha
V
Tar
Krisztina
K
Orthofer
Michael
M
Neely
G Gregory
GG
Dietzl
Georg
G
Manoukian
Armen
A
Funovics
Martin
M
Prager
Gerhard
G
Wagner
Oswald
O
Ferrandon
Dominique
D
Aberger
Fritz
F
Hui
Chi-chung
CC
Esterbauer
Harald
H
Penninger
Josef M
JM
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
D029721:Drosophila Proteins; D005938:Glucocorticoids; D053823:Hedgehog Proteins; D012097:Repressor Proteins; C490763:Sufu protein, mouse; C077245:hh protein, Drosophila; D000242:Cyclic AMP