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 conditions of starvation, Sir2 mutant larvae survive better than wild type under conditions of amino-acid starvation as long as sugars are provided. Our findings point to a Sir2-mediated pathway that activates a catabolic response to amino-acid starvation irrespective of the sugar content of the diet.
Obesity is a major problem in affluent societies. In addition to dietary intake, there are clearly genetic factors that make some people more likely to become obese. At present, we have a poor understanding of what the genetic differences are that predispose some individuals to obesity. In order to discover genes that regulate the amount of stored fat, we have conducted a study using larvae of the fruit fly Drosophila and shown that 66 different genes, when mutated, cause these larvae to store more fat. For the majority of these genes, very similar genes exist in humans. We have also shown that the Sir2 gene has a role in protecting these larvae from storing excessive amounts of fat and that it does so by regulating the synthesis and breakdown of fat in individual cells of a tissue where fat is stored. Finally, we demonstrate a role for Sir2 in changing metabolism when certain types of nutrients (amino acids) are lacking in the diet.