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• W2074304856 abstract "Specific neurosecretory cells of the Drosophila brain express insulin-like peptides (dilps), which regulate growth, glucose homeostasis, and aging. Through microarray analysis of flies in which the insulin-producing cells (IPCs) were ablated, we identified a target gene, target of brain insulin (tobi), that encodes an evolutionarily conserved α-glucosidase. Flies with lowered tobi levels are viable, whereas tobi overexpression causes severe growth defects and a decrease in body glycogen. Interestingly, tobi expression is increased by dietary protein and decreased by dietary sugar. This pattern is reminiscent of mammalian glucagon secretion, which is increased by protein intake and decreased by sugar intake, suggesting that tobi is regulated by a glucagon analog. tobi expression is also eliminated upon ablation of neuroendocrine cells that produce adipokinetic hormone (AKH), an analog of glucagon. tobi is thus a target of the insulin- and glucagon-like signaling system that responds oppositely to dietary protein and sugar. Specific neurosecretory cells of the Drosophila brain express insulin-like peptides (dilps), which regulate growth, glucose homeostasis, and aging. Through microarray analysis of flies in which the insulin-producing cells (IPCs) were ablated, we identified a target gene, target of brain insulin (tobi), that encodes an evolutionarily conserved α-glucosidase. Flies with lowered tobi levels are viable, whereas tobi overexpression causes severe growth defects and a decrease in body glycogen. Interestingly, tobi expression is increased by dietary protein and decreased by dietary sugar. This pattern is reminiscent of mammalian glucagon secretion, which is increased by protein intake and decreased by sugar intake, suggesting that tobi is regulated by a glucagon analog. tobi expression is also eliminated upon ablation of neuroendocrine cells that produce adipokinetic hormone (AKH), an analog of glucagon. tobi is thus a target of the insulin- and glucagon-like signaling system that responds oppositely to dietary protein and sugar. All organisms need energy and nutrients to support development, growth, and reproduction. In multicellular animals, communication between specialized organ systems enables the body to adapt to varying food conditions. Sensory organs receive initial inputs on the availability and suitability of nutrients, and upon food intake, the nutritional information is relayed to the neuroendocrine system. This in turn modulates physiologic response based on the type of nutrient taken in and the body's metabolic needs. In mammals, one of the most important systems for controlling metabolism consists of the antagonistic actions of insulin and glucagon (Freychet, 1990Freychet P. Pancreatic hormones.in: Hormones: From Molecules to Disease. Chapman and Hall, New York1990: 697Google Scholar, Ganong, 1991Ganong W.F. Review of Medical Physiology.Fifteenth Edition. Appleton and Lange, Norwalk, CT, USA1991Google Scholar). Upon high sugar intake, insulin is secreted by pancreatic β cells to maintain glucose homeostasis. When blood glucose is low, glucagon is secreted by pancreatic α cells, which causes the release of glucose from glycogen breakdown. The antagonism is not strict, however, since amino acids positively modulate both insulin and glucagon secretion. The coordinated activities of insulin and glucagon represent a key regulatory network that controls body metabolism, and its failure to function properly can result in severe disease conditions such as diabetes. Insulin- and glucagon-like peptides have also been found in Drosophila, where they are represented by the seven DILPs (Brogiolo et al., 2001Brogiolo W. Stocker H. Ikeya T. Rintelen F. Fernandez R. Hafen E. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control.Curr. Biol. 2001; 11: 213-221Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar, Cao and Brown, 2001Cao C. Brown M.R. Localization of an insulin-like peptide in brains of two flies.Cell Tissue Res. 2001; 304: 317-321Crossref PubMed Scopus (127) Google Scholar) and adipokinetic hormone (AKH), respectively (Wu and Brown, 2006Wu Q. Brown M.R. Signaling and function of insulin-like peptides in insects.Annu. Rev. Entomol. 2006; 51: 1-24Crossref PubMed Scopus (360) Google Scholar). Three dilps are expressed in the median neurosecretory cells of the brain, whereas akh is expressed in an endocrine tissue called the corpora cardiaca (CC). The two cell types are directly connected by axons of the insulin-producing cells (IPCs) that project to the CC (Rulifson et al., 2002Rulifson E.J. Kim S.K. Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes.Science. 2002; 296: 1118-1120Crossref PubMed Scopus (775) Google Scholar), reminiscent of the close association between the α and β cells of the pancreas. Ablation of IPCs results in increased hemolymph glucose levels and, interestingly, an increase in life span (Broughton et al., 2005Broughton S.J. Piper M.D. Ikeya T. Bass T.M. Jacobson J. Driege Y. Martinez P. Hafen E. Withers D.J. Leevers S.J. Partridge L. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands.Proc. Natl. Acad. Sci. USA. 2005; 102: 3105-3110Crossref PubMed Scopus (558) Google Scholar, Wessells et al., 2004Wessells R.J. Fitzgerald E. Cypser J.R. Tatar M. Bodmer R. Insulin regulation of heart function in aging fruit flies.Nat. Genet. 2004; 36: 1275-1281Crossref PubMed Scopus (236) Google Scholar). Dysregulation of glucose homeostasis is also observed when akh-expressing cells are ablated (Kim and Rulifson, 2004Kim S.K. Rulifson E.J. Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells.Nature. 2004; 431: 316-320Crossref PubMed Scopus (300) Google Scholar, Lee and Park, 2004Lee G. Park J.H. Hemolymph sugar homeostasis and starvation-induced hyperactivity affected by genetic manipulations of the adipokinetic hormone-encoding gene in Drosophila melanogaster.Genetics. 2004; 167: 311-323Crossref PubMed Scopus (405) Google Scholar). These findings suggest that the insulin-glucagon system of mammals and the DILP-AKH system of Drosophila may have analogous roles in regulating metabolism. Little is known about the genomic targets through which DILP and AKH signaling act. Targets of AKH signaling have not been addressed, while tissue culture studies have identified genes regulated by dFOXO, a transcription factor that mediates DILP signaling. These studies have demonstrated, for example, that genes encoding the Drosophila insulin receptor (dinr) and a translational regulator, d4e-bp, are directly activated by dFOXO (Jünger et al., 2003Jünger M.A. Rintelen F. Stocker H. Wasserman J.D. Vegh M. Radimerski T. Greenberg M.E. Hafen E. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling.J. Biol. 2003; 2: 20Crossref PubMed Google Scholar, Puig et al., 2003Puig O. Marr M.T. Ruhf M.L. Tjian R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.Genes Dev. 2003; 17: 2006-2020Crossref PubMed Scopus (442) Google Scholar). However, dFOXO is likely not the sole mediator of insulin signaling, and these studies cannot address paracrine or endocrine effects. We previously took a complementary approach by using whole organisms to identify genes regulated by different nutrient conditions (Bauer et al., 2006Bauer M. Katzenberger J.D. Hamm A.C. Bonaus M. Zinke I. Jaekel J. Pankratz M.J. Purine and folate metabolism as a potential target of sex-specific nutrient allocation in Drosophila and its implication for lifespan-reproduction tradeoff.Physiol. Genomics. 2006; 25: 393-404Crossref PubMed Scopus (28) Google Scholar, Zinke et al., 2002Zinke I. Schutz C.S. Katzenberger J.D. Bauer M. Pankratz M.J. Nutrient control of gene expression in Drosophila: microarray analysis of starvation and sugar-dependent response.EMBO J. 2002; 21: 6162-6173Crossref PubMed Scopus (301) Google Scholar). Both dinr and d4e-bp were also identified as being nutrient-dependent genes, but each had a distinct expression profile in response to starvation and sugar diets. Genes regulated in a more complex manner were also found, indicating regulatory inputs by multiple nutrient signals. These issues are particularly relevant in vivo since animals rarely take in pure nutrient in terms of, for example, sugars or proteins. In this paper, we have used a combination of genomic and neuroendocrine approaches to characterize a peripheral target of insulin and glucagon signaling in Drosophila. We have identified an evolutionarily conserved α-glucosidase whose transcriptional regulation is dependent on the activities of both DILP- and AKH-producing cells. Its activation occurs through a dFOXO-independent mechanism, and its level is oppositely modulated by dietary amino acid and sugar levels. These results have relevance for understanding how the neuroendocrine system integrates multiple nutrient signals to regulate life span and metabolism. The IPCs send axons to various tissues, including the CC (Ikeya et al., 2002Ikeya T. Galic M. Belawat P. Nairz K. Hafen E. Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila.Curr. Biol. 2002; 12: 1293-1300Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar, Rulifson et al., 2002Rulifson E.J. Kim S.K. Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes.Science. 2002; 296: 1118-1120Crossref PubMed Scopus (775) Google Scholar; Figures 1A–1E). Three of the seven dilps are coexpressed in the IPCs: dilp2 and dilp5 are expressed uniformly throughout the different larval stages, whereas dilp3 increases steadily during larval development (Broughton et al., 2005Broughton S.J. Piper M.D. Ikeya T. Bass T.M. Jacobson J. Driege Y. Martinez P. Hafen E. Withers D.J. Leevers S.J. Partridge L. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands.Proc. Natl. Acad. Sci. USA. 2005; 102: 3105-3110Crossref PubMed Scopus (558) Google Scholar, Ikeya et al., 2002Ikeya T. Galic M. Belawat P. Nairz K. Hafen E. Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila.Curr. Biol. 2002; 12: 1293-1300Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar, Rulifson et al., 2002Rulifson E.J. Kim S.K. Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes.Science. 2002; 296: 1118-1120Crossref PubMed Scopus (775) Google Scholar; see also Figure S1 available online). We generated a dilp3 promoter-Gal4 line that, in combination with UAS-reaper (UAS-RPR) and UAS-head involution defective (UAS-HID), ablates IPCs specifically at the postlarval stage (Figures 1I–1K). Larval IPCs were not ablated (Figures 1F–1H) in this line, and larval growth and viability were not affected (data not shown). To identify the transcriptional targets of signals emanating from the IPCs, we performed microarray analysis of IPC-ablated adult female flies versus control flies kept on a yeast paste diet for 48 hr. There was a dramatic change in CG11909, a gene predicted to be involved in carbohydrate metabolism: this gene was downregulated over 17-fold in IPC-ablated flies as compared to controls (Figure 1L). This was striking in that it was not only the most regulated gene but also the only gene regulated to this degree. The next highest regulated gene, either up or down, was around 4-fold; this included CG9468, which was upregulated and encodes an α-mannosidase. Both RT-PCR and quantitative PCR analysis (Figures 1M and 1N) supported the microarray data for CG11909, which we have termed target of brain insulin (tobi). Using UAS-RPR alone showed an intermediate repression of tobi, consistent with our results showing partial ablation of IPCs when UAS-RPR alone was used (Figures 1J and 1M). Using UAS-HID alone also resulted in repression of tobi expression (Figure 1M). Destruction of IPCs is not a necessity for suppression of tobi since expression of tetanus toxin light chain (TeTxLc), which blocks synaptic transmission (Sweeney et al., 1995Sweeney S.T. Broadie K. Keane J. Niemann H. O'Kane C.J. Targeted expression of tetanus toxin light chain in Drosophila specifically eliminates synaptic transmission and causes behavioral defects.Neuron. 1995; 14: 341-351Abstract Full Text PDF PubMed Scopus (624) Google Scholar), also resulted in downregulation of tobi expression (Figure 1M). To determine whether these results could be attributable to dilp transcription within the IPCs, we generated different lines of UAS-dilp3 RNAi constructs and expressed them in IPCs using the dilp3 promoter (InsP3-Gal4/UAS-d3Ri). This resulted in a significant decrease in dilp3 transcript levels (Figure 1O), and tobi expression was also eliminated in these flies (Figure 1P). Expression of dilp2 and dilp5 was also downregulated (Figures 1Q and 1R), likely due to the high sequence homology of the three dilps. Driving the UAS-d3Ri construct in the fat body or in specific gut cells did not have a significant effect on tobi expression (Figure S1F). Taken together, these results indicate that dilp activity in the IPCs is required for tobi expression. tobi encodes an α-1,4-glucosidase that is highly conserved in human, mouse, and zebrafish (Figure S2). In situ hybridization of female flies grown on yeast showed that tobi is expressed in a specific region of the gut (Figure 2A, black arrow; Figure 2E). It is also expressed in a small tissue that appears to be fat cells surrounding the posterior region of the gut (Figure 2A, white arrow; Figure 2F); similarly stained cells were also found near the ovaries (Figure 2G). When the IPCs are ablated, expression of tobi in these tissues is eliminated (Figure 2C). Together with the genomic data, these results indicate that tobi is a peripheral target of DILP signaling emanating from the brain. As insulin signaling in mammals is strongly regulated by diet, we asked whether tobi is also regulated by dietary conditions. tobi expression was indeed dependent on diet (Figures 2A, 2B, and 2H), being higher when flies are grown on yeast paste than when flies are grown on fly maintenance food (referred to as “fly food”). When IPCs were ablated, diet no longer had any influence: tobi was repressed regardless of food condition (Figures 2C, 2D, and 2H). It should be pointed out that both food conditions allow complete life cycle of Drosophila, and the choice of food used depends on the specific needs, e.g., females lay many more eggs per unit of time on yeast paste than on fly food. The main difference in macronutrient composition between yeast paste and fly food is the relative concentration of protein versus carbohydrate. Yeast paste is high in protein and low in carbohydrate, whereas fly food is low in protein and high in carbohydrate. To determine how dietary protein and sugar affect tobi expression, we first tested various concentrations of yeast extract in 20% sucrose. As seen in Figure 2I, there was a concentration-dependent decrease of tobi expression with decreasing yeast extract, indicating that protein positively modulates tobi expression. A different protein source, casein, was also effective in increasing tobi expression (Figure 2J). Interestingly, the ability of dietary protein to regulate tobi in a concentration-dependent manner was dependent on the presence of sugar: when sugar was absent, tobi expression remained high and was refractory to changes in dietary protein concentration (Figure 2K). We then modified the dietary sugar concentration while keeping the protein level constant. Decreasing sucrose concentration resulted in increased tobi expression, indicating that sugar represses tobi (Figure 2L). When we tested the effect of sucrose in the complete absence of protein, there was even greater degree of repression than in the presence of yeast extract (Figure 2M). Therefore, sugar can repress tobi in a concentration-dependent manner even in the absence of protein; a similar result was obtained using glucose instead of sucrose (Figure 2N). Again, these regulatory effects were strictly dependent on IPC activity since tobi was repressed in all nutrient conditions when IPCs were ablated (Figures 2O and 2P). Taken together, the results of our analysis revealed a highly sensitive dietary regulation of tobi by the opposing effects of sugar and protein. Upon complete starvation, there is a certain basal level of tobi expression; addition of sugar suppresses tobi from this level, whereas addition of protein increases it. Therefore, the lowest point of tobi expression is under conditions of low protein and high sugar, whereas the highest point occurs under conditions of high protein and low sugar. Since insulin secretion in mammals is positively regulated by both proteins and sugars, these results also hinted that tobi responds to a second nutrient-dependent signaling system in addition to insulin signaling. To date, the only well-characterized transcription factor mediating insulin/insulin-like growth factor (IGF) signaling in Drosophila is dFOXO (Jünger et al., 2003Jünger M.A. Rintelen F. Stocker H. Wasserman J.D. Vegh M. Radimerski T. Greenberg M.E. Hafen E. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling.J. Biol. 2003; 2: 20Crossref PubMed Google Scholar, Kramer et al., 2003Kramer J.M. Davidge J.T. Lockyer J.M. Staveley B.E. Expression of Drosophila FOXO regulates growth and can phenocopy starvation.BMC Dev. Biol. 2003; 3: 5Crossref PubMed Scopus (152) Google Scholar, Puig and Tjian, 2006Puig O. Tjian R. Nutrient availability and growth: regulation of insulin signaling by dFOXO/FOXO1.Cell Cycle. 2006; 5: 503-505Crossref PubMed Scopus (63) Google Scholar). When insulin/IGF signaling is high, dFOXO remains in the cytoplasm; when it is low, dFOXO translocates to the nucleus and activates the transcription of target genes such as dinr and the translational regulator d4e-bp (also known as thor) (Jünger et al., 2003Jünger M.A. Rintelen F. Stocker H. Wasserman J.D. Vegh M. Radimerski T. Greenberg M.E. Hafen E. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling.J. Biol. 2003; 2: 20Crossref PubMed Google Scholar, Puig et al., 2003Puig O. Marr M.T. Ruhf M.L. Tjian R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.Genes Dev. 2003; 17: 2006-2020Crossref PubMed Scopus (442) Google Scholar). These observations implied that dFOXO is localized in the nucleus under conditions in which tobi expression is low (e.g., under starvation, when insulin/IGF signaling is low), suggesting that dFOXO is likely not the activator of tobi. dFOXO could act as a repressor since tobi expression is eliminated when IPCs are ablated. When we tested tobi expression in dfoxo mutants, we observed a decrease in tobi expression (Figure 3A); however, based on above arguments, this decrease is unlikely due to dFOXO functioning as an activator. Rather, we favor the view that this is an indirect effect: since dFOXO can activate dinr in a feedback mechanism (Puig et al., 2003Puig O. Marr M.T. Ruhf M.L. Tjian R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.Genes Dev. 2003; 17: 2006-2020Crossref PubMed Scopus (442) Google Scholar, Puig and Tjian, 2006Puig O. Tjian R. Nutrient availability and growth: regulation of insulin signaling by dFOXO/FOXO1.Cell Cycle. 2006; 5: 503-505Crossref PubMed Scopus (63) Google Scholar), dfoxo mutants could have reduced dINR activity and insulin signaling, leading to decreased tobi expression. To further investigate the role of insulin signaling and dFOXO on tobi regulation, we turned to the larval stage. Adults and larvae have different feeding, growth, and physiological characteristics, and their transcriptional response to specific nutrient conditions can vary significantly (Bauer et al., 2006Bauer M. Katzenberger J.D. Hamm A.C. Bonaus M. Zinke I. Jaekel J. Pankratz M.J. Purine and folate metabolism as a potential target of sex-specific nutrient allocation in Drosophila and its implication for lifespan-reproduction tradeoff.Physiol. Genomics. 2006; 25: 393-404Crossref PubMed Scopus (28) Google Scholar, Zinke et al., 2002Zinke I. Schutz C.S. Katzenberger J.D. Bauer M. Pankratz M.J. Nutrient control of gene expression in Drosophila: microarray analysis of starvation and sugar-dependent response.EMBO J. 2002; 21: 6162-6173Crossref PubMed Scopus (301) Google Scholar). We therefore used a dilp2-Gal4 line (Rulifson et al., 2002Rulifson E.J. Kim S.K. Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes.Science. 2002; 296: 1118-1120Crossref PubMed Scopus (775) Google Scholar) to ablate the IPCs; in contrast to the dilp3-Gal4 line generated in this study, the dilp2-Gal4 line ablates the IPCs during the larval stage and strongly affects larval growth (Rulifson et al., 2002Rulifson E.J. Kim S.K. Nusse R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes.Science. 2002; 296: 1118-1120Crossref PubMed Scopus (775) Google Scholar). Figure 3B shows that tobi is repressed when IPCs are ablated during the larval stage; tobi is also decreased in dfoxo mutant larvae (Figure 3C), consistent with the observations in adults. We then tested tobi expression when constitutively active dFOXO™ (i.e., dFOXO that is constitutively localized to the nucleus) is overexpressed (Hwangbo et al., 2004Hwangbo D.S. Gershman B. Tu M.P. Palmer M. Tatar M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body.Nature. 2004; 429: 562-566Crossref PubMed Scopus (714) Google Scholar). Previous studies have shown that although dfoxo mutants are viable, dfoxo overexpression can cause lethality (Jünger et al., 2003Jünger M.A. Rintelen F. Stocker H. Wasserman J.D. Vegh M. Radimerski T. Greenberg M.E. Hafen E. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling.J. Biol. 2003; 2: 20Crossref PubMed Google Scholar, Kramer et al., 2003Kramer J.M. Davidge J.T. Lockyer J.M. Staveley B.E. Expression of Drosophila FOXO regulates growth and can phenocopy starvation.BMC Dev. Biol. 2003; 3: 5Crossref PubMed Scopus (152) Google Scholar). We did not observe an influence on tobi using arm-Gal4 (low ubiquitous expression), whereas there was repression using ppl-Gal4 (see Experimental Procedures), which drives specific expression in the fat body (Zinke et al., 1999Zinke I. Kirchner C. Chao L.C. Tetzlaff M.T. Pankratz M.J. Suppression of food intake and growth by amino acids in Drosophila: the role of pumpless, a fat body expressed gene with homology to vertebrate glycine cleavage system.Development. 1999; 126: 5275-5284PubMed Google Scholar; Figure 3D). This could be due to the higher level of specific expression in the fat body by the ppl driver line. These results support the view that dFOXO can repress tobi expression. As in adults, tobi expression was higher in larvae grown on yeast paste than in larvae grown on fly food (Figure 3E). These results suggested that insulin/IGF signaling is higher in yeast paste than in fly food, although the sugar content in fly food is higher. This is somewhat counterintuitive since higher sugar is usually associated with higher insulin signaling. On the other hand, it is known in mammals that amino acids also increase insulin secretion. We therefore monitored the expression of d4e-bp and dinr under the two different dietary conditions, since higher levels of these genes correlate with lower insulin signaling (Jünger et al., 2003Jünger M.A. Rintelen F. Stocker H. Wasserman J.D. Vegh M. Radimerski T. Greenberg M.E. Hafen E. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling.J. Biol. 2003; 2: 20Crossref PubMed Google Scholar, Puig et al., 2003Puig O. Marr M.T. Ruhf M.L. Tjian R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.Genes Dev. 2003; 17: 2006-2020Crossref PubMed Scopus (442) Google Scholar, Wang et al., 2005Wang M.C. Bohmann D. Jasper H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling.Cell. 2005; 121: 115-125Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar, Zinke et al., 2002Zinke I. Schutz C.S. Katzenberger J.D. Bauer M. Pankratz M.J. Nutrient control of gene expression in Drosophila: microarray analysis of starvation and sugar-dependent response.EMBO J. 2002; 21: 6162-6173Crossref PubMed Scopus (301) Google Scholar). Both genes were expressed at a higher level in fly food than in yeast (Figures 3E and 3F), suggesting a higher level of insulin signaling in yeast paste than in fly food. Since subcellular localization of dFOXO is dependent on insulin signaling, we next monitored dFOXO localization in the fat body under different nutrient conditions (Figure 4). In fly food (high sugar/low protein) and in 20% sugar diet, dFOXO was almost uniformly distributed between the nucleus and cytoplasm. Interestingly, a diet of pure yeast paste (high protein/low sugar) also resulted in uniform distribution, suggesting that a high-protein diet results in high insulin signaling. By contrast, and as expected, dFOXO was strongly localized to the nucleus under complete starvation. We also used tGPH localization to the membranes as a measure of insulin signaling, where higher membrane association correlates with higher signaling (Britton et al., 2002Britton J.S. Lockwood W.K. Li L. Cohen S.M. Edgar B.A. Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions.Dev. Cell. 2002; 2: 239-249Abstract Full Text Full Text PDF PubMed Scopus (486) Google Scholar). As shown in Figure 4B, the degree of membrane localization appears greater in yeast than in 20% sugar (see also Figure S3). Taking these results together with the earlier quantitative analysis of d4e-bp and dinr expression levels, the emerging view is that insulin signaling is higher in high-protein than in high-sugar conditions in Drosophila larvae. Previous studies have demonstrated that reducing insulin signaling extends life span (Broughton et al., 2005Broughton S.J. Piper M.D. Ikeya T. Bass T.M. Jacobson J. Driege Y. Martinez P. Hafen E. Withers D.J. Leevers S.J. Partridge L. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands.Proc. Natl. Acad. Sci. USA. 2005; 102: 3105-3110Crossref PubMed Scopus (558) Google Scholar, Clancy et al., 2001Clancy D.J. Gems D. Harshman L.G. Oldham S. Stocker H. Hafen E. Leevers S.J. Partridge L. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein.Science. 2001; 292: 104-106Crossref PubMed Scopus (1071) Google Scholar, Giannakou et al., 2004Giannakou M.E. Goss M. Junger M.A. Hafen E. Leevers S.J. Partridge L. Long-lived Drosophila with overexpressed dFOXO in adult fat body.Science. 2004; 305: 361Crossref PubMed Scopus (432) Google Scholar, Hwangbo et al., 2004Hwangbo D.S. Gershman B. Tu M.P. Palmer M. Tatar M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body.Nature. 2004; 429: 562-566Crossref PubMed Scopus (714) Google Scholar, Tatar et al., 2001Tatar M. Kopelman A. Epstein D. Tu M.P. Yin C.M. Garofalo R.S. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function.Science. 2001; 292: 107-110Crossref PubMed Scopus (1170) Google Scholar, Wessells et al., 2004Wessells R.J. Fitzgerald E. Cypser J.R. Tatar M. Bodmer R. Insulin regulation of heart function in aging fruit flies.Nat. Genet. 2004; 36: 1275-1281Crossref PubMed Scopus (236) Google Scholar). Since ablating IPCs resulted in a marked reduction of tobi expression, and since tobi expression was highly dependent on food condition, we asked whether IPC ablation would have different effects on life span under different food conditions. Life span was extended in IPC-ablated flies relative to control flies, but only on yeast paste and not on fly food (Figures 5A and 5B). We also measured several physiological parameters, which indicated that IPC-ablated flies are compromised in their ability to adapt to differing food conditions (Figure S4). Interestingly, in contrast to a previous study in which life-span extension upon IPC ablation was accompanied by decreased fecundity (Broughton et al., 2005Broughton S.J. Piper M.D. Ikeya T. Bass T.M. Jacobson J. Driege Y. Martinez P. Hafen E. Withers D.J. Leevers S.J. Partridge L. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands.Proc. Natl. Acad. Sci. USA. 2005; 102: 3105-3110Crossref PubMed Scopus (558) Google Scholar), we did not observe any significant difference in fecundity (Figure S4G). The difference between the two studies most likely lies in the different reagents used—i.e., a weak dilp2 promoter used in earlier studies and our dilp3 promoter may differ in timing, pattern, and/or level of gene expression. Since tobi is reduced upon IPC ablation, and since this results in life-span extension on a yeast paste diet, we next asked whether r" @default.
• W2074304856 created "2016-06-24" @default.
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• W2074304856 date "2008-04-01" @default.
• W2074304856 modified "2023-09-27" @default.
• W2074304856 title "Opposing Effects of Dietary Protein and Sugar Regulate a Transcriptional Target of Drosophila Insulin-like Peptide Signaling" @default.
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