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Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz.

Hull-Thompson J, Muffat J, Sanchez D, Walker DW, Benzer S, Ganfornina MD, Jasper H - PLoS Genet. (2009)

Bottom Line: Loss of NLaz function reduces stress resistance and lifespan, while its over-expression represses growth, promotes stress tolerance and extends lifespan--phenotypes that are consistent with reduced IIS activity.Our results show that JNK-NLaz signaling antagonizes IIS and is critical for metabolic adaptation of the organism to environmental challenges.The JNK pathway and Lipocalins are structurally and functionally conserved, suggesting that similar interactions represent an evolutionarily conserved system for the control of metabolic homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Rochester, Rochester, New York, United States of America.

ABSTRACT
Metabolic homeostasis in metazoans is regulated by endocrine control of insulin/IGF signaling (IIS) activity. Stress and inflammatory signaling pathways--such as Jun-N-terminal Kinase (JNK) signaling--repress IIS, curtailing anabolic processes to promote stress tolerance and extend lifespan. While this interaction constitutes an adaptive response that allows managing energy resources under stress conditions, excessive JNK activity in adipose tissue of vertebrates has been found to cause insulin resistance, promoting type II diabetes. Thus, the interaction between JNK and IIS has to be tightly regulated to ensure proper metabolic adaptation to environmental challenges. Here, we identify a new regulatory mechanism by which JNK influences metabolism systemically. We show that JNK signaling is required for metabolic homeostasis in flies and that this function is mediated by the Drosophila Lipocalin family member Neural Lazarillo (NLaz), a homologue of vertebrate Apolipoprotein D (ApoD) and Retinol Binding Protein 4 (RBP4). Lipocalins are emerging as central regulators of peripheral insulin sensitivity and have been implicated in metabolic diseases. NLaz is transcriptionally regulated by JNK signaling and is required for JNK-mediated stress and starvation tolerance. Loss of NLaz function reduces stress resistance and lifespan, while its over-expression represses growth, promotes stress tolerance and extends lifespan--phenotypes that are consistent with reduced IIS activity. Accordingly, we find that NLaz represses IIS activity in larvae and adult flies. Our results show that JNK-NLaz signaling antagonizes IIS and is critical for metabolic adaptation of the organism to environmental challenges. The JNK pathway and Lipocalins are structurally and functionally conserved, suggesting that similar interactions represent an evolutionarily conserved system for the control of metabolic homeostasis.

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JNK regulates transcription of NLaz.(A, B) Real time PCR measuring transcript levels of puc and NLaz in whole larvae (A) and dissected fatbody (B). Larvae express Hepact under the control of the ubiquitous T80-Gal4 driver (A) or the fatbody pplG4 driver (B) combined with tubGal80ts. Genotypes: (A) w1118; T80Gal4, tubGal80ts/UAS-Hepact; control genotype: w1118; T80Gal4, tubGal80ts/+; (B) w1118; pplGal4, tubGal80ts/UAS-Hepact; control genotype: w1118; pplGal4, tubGal80ts/+. Larvae were reared at 18°C until 96 hours after egg laying, heat shocked for 1.5 hours at 37°C and left at 29°C for 6 hours (A) or 3 hours (B) to activate the driver. Transcript levels are normalized to rp49. Averages and Standard Deviations of three independent experiments are shown. p values were calculated using Student's T test.
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pgen-1000460-g002: JNK regulates transcription of NLaz.(A, B) Real time PCR measuring transcript levels of puc and NLaz in whole larvae (A) and dissected fatbody (B). Larvae express Hepact under the control of the ubiquitous T80-Gal4 driver (A) or the fatbody pplG4 driver (B) combined with tubGal80ts. Genotypes: (A) w1118; T80Gal4, tubGal80ts/UAS-Hepact; control genotype: w1118; T80Gal4, tubGal80ts/+; (B) w1118; pplGal4, tubGal80ts/UAS-Hepact; control genotype: w1118; pplGal4, tubGal80ts/+. Larvae were reared at 18°C until 96 hours after egg laying, heat shocked for 1.5 hours at 37°C and left at 29°C for 6 hours (A) or 3 hours (B) to activate the driver. Transcript levels are normalized to rp49. Averages and Standard Deviations of three independent experiments are shown. p values were calculated using Student's T test.

Mentions: To identify potential mediators of JNK-induced metabolic changes, we tested the transcriptional response of a number of candidate genes to JNK activation. We focused on the putative adipokines and secreted regulators of Insulin signaling, dALS, IMP-L2, GLaz, Karl, and NLaz, since these molecules or their mammalian homologues have been implicated in systemically governing metabolic homeostasis. Activation of JNK was achieved by over-expression of a constitutively active Hep (Hepact) in larvae using the TARGET system, which allows heat-inducible expression of UAS-linked transgenes [43]. We expressed Hepact ubiquitously (using the ubiquitous driver T80-Gal4), or specifically in the fatbody (using the fatbody driver ppl-Gal4, expressed both in larval and adult fatbody, [36] and Figure S8), for a short period of time, increasing the likelihood of observing direct transcriptional effects of increased JNK activity. Transcript levels of potential JNK target genes were then assessed by real-time RT-PCR (Figure 2 and Figure S2A).


Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz.

Hull-Thompson J, Muffat J, Sanchez D, Walker DW, Benzer S, Ganfornina MD, Jasper H - PLoS Genet. (2009)

JNK regulates transcription of NLaz.(A, B) Real time PCR measuring transcript levels of puc and NLaz in whole larvae (A) and dissected fatbody (B). Larvae express Hepact under the control of the ubiquitous T80-Gal4 driver (A) or the fatbody pplG4 driver (B) combined with tubGal80ts. Genotypes: (A) w1118; T80Gal4, tubGal80ts/UAS-Hepact; control genotype: w1118; T80Gal4, tubGal80ts/+; (B) w1118; pplGal4, tubGal80ts/UAS-Hepact; control genotype: w1118; pplGal4, tubGal80ts/+. Larvae were reared at 18°C until 96 hours after egg laying, heat shocked for 1.5 hours at 37°C and left at 29°C for 6 hours (A) or 3 hours (B) to activate the driver. Transcript levels are normalized to rp49. Averages and Standard Deviations of three independent experiments are shown. p values were calculated using Student's T test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2667264&req=5

pgen-1000460-g002: JNK regulates transcription of NLaz.(A, B) Real time PCR measuring transcript levels of puc and NLaz in whole larvae (A) and dissected fatbody (B). Larvae express Hepact under the control of the ubiquitous T80-Gal4 driver (A) or the fatbody pplG4 driver (B) combined with tubGal80ts. Genotypes: (A) w1118; T80Gal4, tubGal80ts/UAS-Hepact; control genotype: w1118; T80Gal4, tubGal80ts/+; (B) w1118; pplGal4, tubGal80ts/UAS-Hepact; control genotype: w1118; pplGal4, tubGal80ts/+. Larvae were reared at 18°C until 96 hours after egg laying, heat shocked for 1.5 hours at 37°C and left at 29°C for 6 hours (A) or 3 hours (B) to activate the driver. Transcript levels are normalized to rp49. Averages and Standard Deviations of three independent experiments are shown. p values were calculated using Student's T test.
Mentions: To identify potential mediators of JNK-induced metabolic changes, we tested the transcriptional response of a number of candidate genes to JNK activation. We focused on the putative adipokines and secreted regulators of Insulin signaling, dALS, IMP-L2, GLaz, Karl, and NLaz, since these molecules or their mammalian homologues have been implicated in systemically governing metabolic homeostasis. Activation of JNK was achieved by over-expression of a constitutively active Hep (Hepact) in larvae using the TARGET system, which allows heat-inducible expression of UAS-linked transgenes [43]. We expressed Hepact ubiquitously (using the ubiquitous driver T80-Gal4), or specifically in the fatbody (using the fatbody driver ppl-Gal4, expressed both in larval and adult fatbody, [36] and Figure S8), for a short period of time, increasing the likelihood of observing direct transcriptional effects of increased JNK activity. Transcript levels of potential JNK target genes were then assessed by real-time RT-PCR (Figure 2 and Figure S2A).

Bottom Line: Loss of NLaz function reduces stress resistance and lifespan, while its over-expression represses growth, promotes stress tolerance and extends lifespan--phenotypes that are consistent with reduced IIS activity.Our results show that JNK-NLaz signaling antagonizes IIS and is critical for metabolic adaptation of the organism to environmental challenges.The JNK pathway and Lipocalins are structurally and functionally conserved, suggesting that similar interactions represent an evolutionarily conserved system for the control of metabolic homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Rochester, Rochester, New York, United States of America.

ABSTRACT
Metabolic homeostasis in metazoans is regulated by endocrine control of insulin/IGF signaling (IIS) activity. Stress and inflammatory signaling pathways--such as Jun-N-terminal Kinase (JNK) signaling--repress IIS, curtailing anabolic processes to promote stress tolerance and extend lifespan. While this interaction constitutes an adaptive response that allows managing energy resources under stress conditions, excessive JNK activity in adipose tissue of vertebrates has been found to cause insulin resistance, promoting type II diabetes. Thus, the interaction between JNK and IIS has to be tightly regulated to ensure proper metabolic adaptation to environmental challenges. Here, we identify a new regulatory mechanism by which JNK influences metabolism systemically. We show that JNK signaling is required for metabolic homeostasis in flies and that this function is mediated by the Drosophila Lipocalin family member Neural Lazarillo (NLaz), a homologue of vertebrate Apolipoprotein D (ApoD) and Retinol Binding Protein 4 (RBP4). Lipocalins are emerging as central regulators of peripheral insulin sensitivity and have been implicated in metabolic diseases. NLaz is transcriptionally regulated by JNK signaling and is required for JNK-mediated stress and starvation tolerance. Loss of NLaz function reduces stress resistance and lifespan, while its over-expression represses growth, promotes stress tolerance and extends lifespan--phenotypes that are consistent with reduced IIS activity. Accordingly, we find that NLaz represses IIS activity in larvae and adult flies. Our results show that JNK-NLaz signaling antagonizes IIS and is critical for metabolic adaptation of the organism to environmental challenges. The JNK pathway and Lipocalins are structurally and functionally conserved, suggesting that similar interactions represent an evolutionarily conserved system for the control of metabolic homeostasis.

Show MeSH
Related in: MedlinePlus