Using a novel high throughput method we were able to interrogate over 10,000 genes (75%) for their ability to influence fat levels in living adult Drosophila (fruit fly). As most of these genes have mouse and human homologues, the findings are providing a platform of new potential therapeutic targets for testing and development in mammals. One of the top hits was the hedgehog signaling pathway. Switching to a mammalian model, and now in collaboration with Harry Esterbauer at the MUW, we produced hedgehog mutant mice. Intriguingly, these Ap2SufuKO mice have virtually no fat tissue. They are the first completely healthy lipoatrophic model generated to date and carry important implications towards our understanding of metabolic regulation as well as towards therapeutic management of human lipodystrophies. One unique aspect of “hedgehog” control of fat biology is selectivity to block development of white, but not brown fat. In the accompanying figure, the hedgehog pathway in white and brown fat stem cells was genetically activated (green). The white fat stem cells never give up their fibroblast-like appearance whereas the brown cells differentiate fully, with a full compliment of grape-like lipid droplet clusters. As brown fat is often considered “good fat”, and white considered “bad fat”, the work identifies hedgehog as one of the first promoters of “good” fat development.