From Flies to Mice: Drosophila as a Model System to Study Fat Biology
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Adipose tissues are found in a wide range of animal species ranging from invertebrates to mammals and are essential for many aspects of the animal life cycle. Fat biology has taken on a new and urgent importance as it is intimately linked to one of the most prevelant and costly health problems of our time - obesity. Model organisms are a powerful resource for the discovery of genes critical to human health and disease. Thus far, the utility of Drosophila melanogaster as a model system to study fat biology has not been critically evaluated. My studies highlight the potential of this system to uncover new genes and pathways that may impact our current understanding of adipose biology. Hedgehog signals regulate invertebrate and vertebrate development, yet the role of the cascade in adipose development was undefined. I found that fat body specific transgenic activation of Hedgehog signaling inhibited fly fat formation. Conversely, fat body specific Hedgehog blockade stimulated fly fat formation. Strikingly, the anti-adipogenic effect of Hedgehog signaling was conserved in mammalian adipogenic models in both sufficiency and necessity tests. Hedgehog signals elicit this function early in adipogenesis, upstream of PPARgamma, potentially acting as a molecular switch diverting preadipocytes and mesenchymal prescursors away from adipogenesis and towards osteogenesis. In another study, I investigated the role of Adipose, an evolutionarily conserved gene isolated from naturally occurring obese flies. Through gain- and loss-of-function studies in flies, mammalian cell culture, and mice I showed that the Adipose pathway plays a conserved role in obesity and diabetes. Furthermore, I found that Adipose controls the activity of PPARgamma, a central regulator of adipogenesis and the target of the thiazolidinedione class of anti-diabetic drugs. Adipose inhibits PPARgamma function by directly binding Med23, a component of the Mediator Complex, which connects transcription factors with RNA polymerase II. Taken together, I have shown that both the Hh and Adp pathway have evolutionary conserved functions in fat formation. These results support the idea that Drosophila is a useful system to study adipose biology and discoveries in flies will lead to biological insights relevant to mammals and the treatment of obesity and diabetes.