Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate

Pospisilik, J. Andrew Schramek, Daniel Schnidar, Harald Cronin, Shane J.F. Nehme, Nadine T. Zhang, Xiaoyun Knauf, Claude Cani, Patrice D. [UCL] Aumayr, Karin Todoric, Jelena Aberger, Fritz Hiu, Chi-chung Esterbauer, Harald Penninger, Josef M. Bayer, Martina Haschemi, Arvand Puviindran, Vijitha Tar, Krisztina Orthofer, Michael Neely, G. Gregory Dietzl, Georg Manoukian, Armen Funovics, Martin Prager, Gerhard Ferrandon, Dominique et al.[show all]

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 similar to 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.