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.

DOI: 10.1016/j.cell.2009.12.027

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@article{Pospisilik2010DrosophilaGO, title={Drosophila Genome-wide Obesity Screen Reveals Hedgehog as a Determinant of Brown versus White Adipose Cell Fate}, author={J. Andrew Pospisilik and Daniel Schramek and Harald Schnidar and Shane J.F. Cronin and Nadine T. Nehme and Xiaoyun Zhang and Claude Knauf and Patrice D. Cani and Karin Aumayr and Jelena Todoric and Martina Bayer and Arvand Haschemi and Vijitha Puviindran and Krisztina Tar and Michael Orthofer and G. Gregory Neely and Georg Dietzl and Armen Manoukian and Martin Funovics and Gerhard Prager and Oswald Wagner and Dominique Ferrandon and Fritz Aberger and Chi-chung Hui and Harald Esterbauer and Josef M. Penninger}, journal={Cell}, year={2010}, volume={140}, pages={148-160} }