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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Aging Cell. Author manuscript; available in PMC Aug 14, 2009.
Published in final edited form as:
PMCID: PMC2727449
NIHMSID: NIHMS126593

JNK signaling in insulin-producing cells is required for adaptive responses to stress in Drosophila

Summary

Adaptation to environmental challenges is critical for survival of an organism. Repression of Insulin/IGF Signaling (IIS) by stress-responsive Jun-N-terminal Kinase (JNK) signaling is emerging as a conserved mechanism that allows reallocating resources from anabolic to repair processes under stress conditions. JNK activation in Insulin producing cells (IPCs) is sufficient to repress Insulin and Insulin-like peptide (ILP) expression in rats and flies, but the significance of this interaction for adaptive responses to stress is unclear. Here we show that JNK activity in IPCs of flies is required for oxidative stress-induced repression of the Drosophila ILP2. We find that this repression is required for growth adaptation to heat stress as well as adult oxidative stress tolerance, and that induction of stress response genes in the periphery is in part dependent on IPC-specific JNK activity. Endocrine control of IIS by JNK in IPCs is thus critical for systemic adaptation to stress.

Keywords: JNK, Insulin, stress response, Drosophila, metabolism, growth

Introduction

Metabolic adaptation to environmental challenges is imperative for the long-term homeostasis and reproductive success of metazoans. Ectotherms, which are particularly vulnerable to environmental changes, have evolved particularly strong adaptive responses (termed diapause, (Tatar & Yin 2001; Denlinger 2002)), but metabolic adaptation to stress is also conserved in higher organisms, including vertebrates (Buteau et al. 2007; Russell & Kahn 2007; Schumacher et al. 2008).

The molecular regulation of metabolic adaptation is only starting to be understood. Studies in C.elegans have established the evolutionarily conserved Insulin/IGF Signaling (IIS) pathway as a central regulator of metabolic adaptation, controlling the transition into a larval diapause, the dauer state (Kimura et al. 1997; Burnell et al. 2005; Kenyon 2005). The same signaling pathway controls stress tolerance and metabolic homeostasis in higher organisms, influencing lifespan (Tatar & Yin 2001; Denlinger 2002; Bishop & Guarente 2007a; Russell & Kahn 2007; Sim & Denlinger 2008; Taguchi & White 2008), but the mechanism(s) by which IIS activity is modulated in response to stress remain to be established.

Recent work in flies, worms and mice suggest that stress signaling pathways play an important role in this regulation, increasing lifespan and stress tolerance by repressing IIS activity (Oh et al. 2005; Wang et al. 2005) (Bishop & Guarente 2007b; Schumacher et al. 2008). Interestingly, a similar antagonism between stress signaling and IIS also seems to be central to the etiology of type II diabetes, suggesting that repression of IIS activity is an important acute response to stress, but has deleterious effects on metabolic homeostasis under chronic conditions (Hotamisligil 2006). In particular, the stress-responsive Jun-N-terminal Kinase (JNK) pathway has been shown to regulate IIS activity at multiple levels, influencing lifespan and stress tolerance in lower organisms and promoting insulin resistance in mouse models for diabetes (Hirosumi et al. 2002; Kaneto et al. 2002; Kajimoto & Kaneto 2004; Oh et al. 2005; Wang et al. 2005; Karpac & Jasper in press). JNK can repress IIS signal transduction by phosphorylating the Insulin receptor substrate, as well as by activating the IIS-regulated transcription factor Foxo, but can also interfere with Insulin-like peptide (ILP) expression in Insulin Producing Cells (IPCs) (Hirosumi et al. 2002; Kaneto et al. 2002; Essers et al. 2004; Kajimoto & Kaneto 2004; Oh et al. 2005; Wang et al. 2005).

The regulation of Insulin-like peptide expression suggests a central role for IPC-specific JNK signaling in coordinating metabolic adaptation systemically, i.e. throughout the whole organism. Insulin-like peptides are produced by pancreatic beta cells in mammals, and by neurosecretory cells in Drosophila and C.elegans (IPCs in Drosophila and ASI and ASJ neurons in worms (Brogiolo et al. 2001; Ikeya et al. 2002; Li et al. 2003). The central role of these neurosecretory cells in metabolic adaptation and lifespan has been established in worms and flies. Ablation of ASI neurons promotes dauer formation (Bargmann & Horvitz 1991), while expression of the Insulin-like peptide daf28 in these neurons is downregulated in response to stress (Li et al. 2003). Furthermore, ablation of IPCs results in flies with diabetic phenotypes, but extended lifespan and increased stress tolerance (Rulifson et al. 2002; Wessells et al. 2004; Broughton et al. 2005), and repressing ILP expression in IPCs by over-expression of either the JNK Kinase Hemipterous (Hep), or a dominant-negative version of p53 results in increased lifespan (Wang et al. 2005; Bauer et al. 2007).

While these studies confirm that forced repression of Insulin-like peptide expression is sufficient to impair IIS activity and increase stress tolerance and longevity, it remains unclear whether this repression is part of an acute adaptive response to environmental stress. Here we show that IPC-specific JNK activity is required for ILP repression in response to oxidative stress in flies, mediating stress-induced growth repression during development and promoting adult stress tolerance. IPC-specific JNK signaling is thus central to systemic adaptive responses to acute environmental challenges.

Results and Discussion

JNK represses dILP2 expression in response to oxidative stress

The increased stress tolerance and extended lifespan of flies in which IPCs are ablated, as well as the repression of dILP2 transcription by JNK signaling in IPCs, suggests that repression of dILPs plays an important role in coordinating stress responses systemically. To test this hypothesis, we analyzed dILP transcript levels in response to treatment with the oxidative stress-inducing compound Paraquat. Supporting a potential role for ILP repression in metabolic adaptation to stress, we observed significant down-regulation of the genes encoding dILP2 and dILP5, while dILP3 expression was not affected (Figure 1). Importantly, stress-induced repression of dILP2 transcription was not observed in flies in which JNK signaling was specifically inhibited in IPCs, by expression of a dominant-negative form of the Drosophila JNK Basket (BskDN)(Weber et al. 2000). Interestingly, dILP5 repression was unaffected in these flies, indicating that JNK signaling is specifically required for the transcriptional control of dILP2 in response to environmental stress (Figure 1). While little is known about the specific functions of different dILPs in the regulation of IIS activity, various studies have demonstrated specific regulation of the encoding genes in response to nutritional cues or to specific signaling events (Ikeya et al. 2002; Hwangbo et al. 2004; Wang et al. 2005; Gershman et al. 2007). Further studies are needed to establish whether this specific regulation of individual dILPs has physiological consequences in vivo, and to assess how individual dILPs would elicit specific responses through the sole Insulin Receptor (InR) encoded in the fly genome.

Figure 1
Reduction of dilp transcription after paraquat treatment is dependent on JNK activity in IPCs

Growth adaptation is regulated by IPC-specific JNK activity

DILP2 has been described as a major regulator of growth in flies, and can alone rescue the growth defects of flies with ablated IPCs (Ikeya et al. 2002; Rulifson et al. 2002), suggesting that its repression by JNK signaling in IPCs significant impacts growth and physiology. To test this, we assessed the requirement for IPC-specific JNK activity in heat-induced growth repression, an adaptive strategy conserving energy resources under adverse conditions. To assess whether IPC-specific JNK activity is required for this response, we compared adult wing sizes of flies reared at 25 °C with wing sizes of flies that were shifted to 29°C early in development. Wild-type animals (OreR) exhibit significantly reduced body weight as well as wing size when shifted to 29°C, caused by a decrease in cell numbers and a slight reduction in cell size (Figure 2 A-E). This phenotype is reminiscent of the consequences of IIS repression, or Foxo activation, which impacts primarily cell proliferation, but also influences cell growth (Junger et al. 2003; Puig et al. 2003). This reduction is less pronounced in mutants for JNKK/Hep (Figure 2 A-E; hep1 is a P-element insertion into the hep locus, resulting in viable hemizygous adult males with deficient JNK activity, (Glise et al. 1995; Wang et al. 2003)). Strikingly, flies expressing BskDN or a double-stranded RNA targeting bsk (BskRNAi; this line efficiently represses bsk transcription; Figure S2) specifically in IPCs (using the IPC specific driver, dilp2G4 (Rulifson et al. 2002)) also exhibited significantly reduced growth repression compared to wild-type controls, demonstrating that IPC-specific JNK is required for growth adaptation (Figure 2 F, G; see also Figure S1). As seen for conditions in which JNK activity is increased in flies (Wang et al. 2003), inhibiting JNK signaling in IPCs does not affect developmental timing, indicating that the observed effects are primarily mediated through a control of cell proliferation (Figure S1C). Importantly, growth repression was also reduced in flies constitutively expressing dILP2 in IPCs, confirming the role of dILP2 repression in this response (Figure 2 F, G). Further highlighting the importance of dILP2 repression downstream of JNK signaling in this adaptive response, we found that co-expressing a double-stranded RNA targeting dILP2 (dILP2RNAi, this lines efficiently reduces dILP2 transcription; Figure S2) was sufficient to rescue the growth repression in animals expressing BskDN in IPCs.

Figure 2
JNK is required in IPC's for stress-induced growth repression

IPC-specific JNK activity regulates systemic stress tolerance

Since IIS regulates both growth during development, as well as stress tolerance in the adult, we asked whether IPC-specific JNK signaling would also influence stress tolerance. We tested the sensitivity of flies expressing BskDN or BskRNAi in IPCs to Paraquat in conditions identical to the ones used in the experiments described in Figure 1 (Figure 3A). Supporting a critical function for IPC-specific JNK activity in systemic stress tolerance, these flies were significantly more sensitive to Paraquat compared to sibling controls. To control for genetic background effects, and to test whether acute rather than chronic repression of JNK activity would be sufficient to induce the observed stress sensitivity, we generated an RU486-inducible IPC-specific Gal4 driver line (using a 1500bp fragment of the dILP2 promoter to drive Gal4 fused to a progesterone binding domain (Osterwalder et al. 2001). This driver specifically and efficiently drives expression of UAS-linked transgenes in IPCs in response to RU486; Figure 3C and data not shown). Expression of BskDN or BskRNAi using this driver increased stress sensitivity of adult flies in a RU486-dependent manner, further supporting the notion that IPC-specific JNK activity is required for adaptive responses and thus increased tolerance to environmental stress (Figure 3B). Importantly, fecundity was not affected in animals expressing BskDN in IPCs, indicating that JNK-mediated repression of dILP2 transcription influences cytoprotective mechanisms directly, and not by compromising reproduction. This view is supported by the fact that fecundity is also not affected in long-lived JNK gain-of-function flies (Wang et al. 2003). Interestingly, inhibiting JNK activity in IPCs does not lead to shortened lifespan under optimal culture conditions (not shown), indicating that JNK activity is not normally required in IPCs, but becomes critical under stress conditions. This observation further suggests that the basal activity of JNK detected in IPCs using a JNK lacZ reporter line (pucE69, (Wang et al. 2005)) is likely a consequence of acute stress responses that result in accumulation of beta-Galactosidase activity in IPCs throughout the lifetime of the animal, and does not demonstrate a requirement for chronic basal JNK activity in these cells.

Figure 3
JNK signaling in IPCs is required for stress tolerance in adults

To confirm that the observed stress sensitivity of flies with IPC-specific inhibition of JNK was caused by a lack of dILP2 repression (as shown in Figure 1), we assessed whether repressing dILP2 transcription constitutively was sufficient to rescue the stress sensitivity of flies with impaired IPC-specific JNK signaling activity (Figure 3D). Indeed, stress tolerance of flies expressing both BskDN and dILP2RNAi was similar to the stress tolerance observed in wild-type control flies, while over-expression of dILP2 resulted in significant increase of oxidative stress sensitivity (Figure 3E). These results further underline the importance of JNK-mediated repression of dILP2 for systemic stress tolerance.

IPC-specific JNK activity is required for peripheral stress responses

Our results suggest that activation of JNK signaling in IPCs increases stress tolerance by inhibiting IIS activity in the periphery. IIS repression results in increased nuclear translocation of the transcription factor Foxo, which promotes the expression of stress response genes and growth regulators (Junger et al. 2003; Puig et al. 2003; Wang et al. 2005; Vihervaara & Puig 2008). To test whether this transcriptional stress response in the periphery was dependent on IPC-specific JNK activity and dILP2 repression, we analyzed the induction of the Foxo target and stress response genes thor, dLip4 and gstD1 in the abdomen and thorax of stressed flies (Figure 4A). Supporting a requirement for IPC-specific JNK activation for systemic transcriptional stress responses, we found that induction of thor, dLip4 and gstD1 was significantly impaired in flies expressing BskDN in the IPCs. We further tested whether nucleo-cytoplasmic distribution of Foxo in abdominal fatbodies would be affected by stress. Indeed, we found that Paraquat exposure resulted in increased nuclear localization of Foxo in abdominal fatbody cells, and, strikingly, that this effect is strongly reduced in flies over-expressing dILP2 in IPCs (Figure 4B). The repression of dILP2 in response to oxidative stress is thus critical for increased nuclear localization and activity of Foxo in peripheral tissues.

Figure 4
JNK signaling in IPCs is required for transcriptional stress response in the periphery

Interestingly, however, while induction of Foxo target genes was significantly reduced, it was not completely abolished in flies expressing BskDN in IPCs, suggesting that IPC-specific JNK activity is important for a sustained and efficient systemic stress response, while local responses to ROS are still functional when JNK is inhibited in IPCs (Figure 4C). Cell autonomous activation of Foxo by JNK signaling has been described in mice and flies (Essers et al. 2004; Oh et al. 2005; Wang et al. 2005; Luo et al. 2007; Nielsen et al. 2008), and it likely plays an important role in cytoprotection and/or apoptosis in response to local insults. Our results suggest that the repression of dILP2 transcription by IPC-specific activity of JNK adds a critical regulatory dimension that allows coordinating cellular stress responses systemically (Figure 4C). Recent work in mice suggests that such a systemic regulation of IIS activity might be an evolutionarily conserved response to damaging stimuli (Niedernhofer et al. 2006; van der Pluijm et al. 2007).

Interestingly, while we find that repression of dILP2 transcription is a critical component of the adaptive systemic response to stress, a recent study reports that constitutively repressing dILP2 transcription is not sufficient to increase stress tolerance of wild-type flies, an observation that is consistent with our own findings (Broughton et al. 2008, and compare wild-type and dilp2>dILP2RNAi in Figure 3D). The lack of increased stress tolerance when dILP2 is repressed constitutively is due to compensatory up-regulation of dILP3 and dILP5 expression in IPCs (Broughton et al. 2008, and Karpac, data not shown). Based on our results reported here, it is evident that such a compensatory induction of dILP3 and dILP5 does not occur immediately after stress exposure and that repression of dILP2 thus promotes stress tolerance under these acute conditions. Accordingly, when repression of dILP2 transcription is impaired, as in IPC-specific JNK loss-of-function conditions, reduced stress tolerance is observed.

Our analysis focuses primarily on oxidative stress as a well-established insult that promotes loss of homeostasis in aging organisms, as well as on growth responses to elevated temperature during development. It remains unclear whether the observed endocrine mechanisms govern adaptive responses to other challenges, such as inflammation or DNA damage. Interestingly, repression of the IIS/GH signaling axis has been described in mice with elevated DNA damage (Schumacher et al. 2008), but the mechanisms mediating this repression have not yet been uncovered. Based on the evolutionary conservation of JNK signaling and of the repression of Insulin production by JNK in rat islet cells (Kaneto et al. 2002), it can be expected that similar endocrine mechanisms might govern the metabolic adaptation to stress in vertebrates.

An interesting question that arises from our observations is whether the adaptive repression of dILP2 expression by stress-induced JNK activation can result in lifespan extension, and whether low level exposure to oxidative stress should therefore extend lifespan. Indeed, we have shown before that lifespan can be extended when JNK is moderately activated in IPCs (Wang et al., 2005), and various studies have shown that moderate exposure to stress can have beneficial effects on the organism's lifespan (an effect termed hormesis, see for example (Hercus et al. 2003)). The regulation discussed here implies a mechanism for such hormetic effects of oxidative stress.

Experimental Procedures

Drosophila strains and fly handling

Fly strains: OreR, from the Bloomington Drosophila stock center; hep1/FM6, gift from S. Noselli; UASBskRNAi and UASDilp2RNAi, from Vienna Drosophila Research Center; UASHepact and UASBskDN, gifts from M. Mlodzik; UASDilp2, gift from E. Hafen; and dilp2Gal4, gift from E.J. Rulifson.

dilp2GS: The dilp2 promoter (1500 bp amplified with 5′-TTC CGT GCG GCC GCG GCC ATG GCG ATG GCG ATG A-3′ and 5′-TTC CGT GCG GCC GCC TTT ACG ATC AAA TGG ATT A-3′) was cloned into the NotI site of pP{UAS-Geneswitch} (Osterwalder et al. 2001). P element-mediated transformation was performed by Genetic Services, Inc.

For paraquat treatments, flies (4-6d old, reared on 12 hr light:dark cycle) were starved for 6 hr and then transferred to vials containing filter paper soaked in 5% sucrose solution with or without 25 mM paraquat (Methyl Viologen, Sigma). Survival was assessed after 24-28hr. Driver and UAS lines were kept in w1118 genetic background.

RU486-induction was performed by feeding flies with 500 μg/ml RU486 in 5% sucrose on filter paper for 1.5 hr. Filter paper was then exchanged for filter paper soaked with 500 μg/ml RU486 and 25 mM paraquat in 5% sucrose. Survival was assessed after 28 hr. Compared genotypes were always treated in parallel.

To assess stress-induced growth response, 30 females and 10 males for each cross were placed in bottles and allowed to mate for 3 days. Next, an equal amount of females from each cross were placed into two vials, and allowed to lay eggs for 16hr at 25°C. The flies were removed from the vials after 16hr, and each vial was kept at 25°C for an additional 24hr. After 24hr, one vial from each cross was transferred to 29°C, the other left at 25°C. Wings (10 per genotype) were collected from male flies (5-7d) and wing area, cell size, and cell number were quantified using Adobe Photoshop.

qRT-PCR analysis

Expression of genes was measured using qRT-PCR. Male, whole flies (0-3d) were processed in Trizol (Invitrogen) to generate total RNA. In experiments using paraquat, flies were processed 16 hrs after starting treatment, ensuring that flies had fed on the provided sucrose/Paraquat solution and allowing time for transcriptional responses to fully engage. One μg of RNA was reverse transcribed using the SuperScript II reverse transcriptase (Invitrogen). Primer sequences are listed in supplementary material. Standard qRT-PCR reaction using SYBR Green was performed on a Bio-Rad iCYCLER iQ. Data is presented as expression relative to actin5C.

Immunohistochemistry

Flies were dissected in fixative (4% Paraformaldehyde in PBS), and fixation was continued for 15 min at room temperature (RT). After washing in PBS/0.1 % Triton, tissues were blocked in BBTr (PBS/0.1%Triton/0.1% BSA) for 1 hr at RT. Primary antibody incubations were performed in BBTr overnight at 4°C (using rabbit anti-Foxo N-term (Puig et al. 2003), at 1:200 dilution). The tissue was then washed in PBTr (2 × 10′ at RT), and incubated for 2hrs at RT with TRITC-labeled secondary antibody and DAPI. Tissues were then mounted in mounting medium and inspected by confocal microscopy (Leica SP5 confocal microscope).

Supplementary Material

Supp Mat Fig S1

Supp Mat Fig S2

Supp Mat Legends

Acknowledgments

This work was supported by the National Institute on Aging (RO1 AG028127 to HJ) and the National Institute of Diabetes and Digestive and Kidney diseases (F32 DK083862 to JK).

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