a buoyancy-based screen of drosophila larvae for fat-storage mutants reveals a role for sir2 in coupling fat storage to nutrient availabilitybuoyancy-based屏幕积聚脂肪突变体果蝇幼虫的揭示了一个角色在耦合sir2脂肪储存营养的可用性.pdfVIP

A Buoyancy-Based Screen of Drosophila Larvae for Fat- Storage Mutants Reveals a Role for Sir2 in Coupling Fat Storage to Nutrient Availability ˆ 1 2 1 Tania Reis *, Marc R. Van Gilst , Iswar K. Hariharan * 1 Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America, 2 Basic Sciences Department, Fred Hutchinson Cancer Research Center, Seattle, Washingon, United States of America Abstract Obesity has a strong genetic component, but few of the genes that predispose to obesity are known. Genetic screens in invertebrates have the potential to identify genes and pathways that regulate the levels of stored fat, many of which are likely to be conserved in humans. To facilitate such screens, we have developed a simple buoyancy-based screening method for identifying mutant Drosophila larvae with increased levels of stored fat. Using this approach, we have identified 66 genes that when mutated increase organismal fat levels. Among these was a sirtuin family member, Sir2. Sirtuins regulate the storage and metabolism of carbohydrates and lipids by deacetylating key regulatory proteins. However, since mammalian sirtuins function in many tissues in different ways, it has been difficult to define their role in energy homeostasis accurately under normal feeding conditions. We show that knockdown of Sir2 in the larval fat body results in increased fat levels. Moreover, using genetic mosaics, we demonstrate that Sir2 restricts fat accumulation in individual cells of the fat body in a cell-autonomous manner. Consistent with this function, changes in the expression of metabolic enzymes in Sir2 mutants point to a shift away from catabolism. Surprisingly, although Sir2 is typically upregulated under conditi