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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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Nlaz acts downstream of JNK to maintain metabolic homeostasis.(A) Percent of male flies surviving after being exposed to prolonged dry starvation. Populations are F1 progeny of crosses between hep1/FM6; pplG4/CyO females and OreR males (hep1/y; pplG4/+; n = 65) or w1118; UAS-NLaz/TM3 males (hep1/y; pplG4/UASNlaz; n = 70). Wild-type controls are F1 progeny of OreR females crossed to w1118 males (OreR/w1118; n = 181). p<0.001 (log rank test) for difference between hep1/y; ppl/+ and either of the other two populations. p = 0.629 (log rank test) for hep1/y; pplG4/UASNLaz compared to OreR/w1118. (B) Glucose and lipid content in homogenates prepared from populations of 10 male flies after 24 hours of wet starvation.
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pgen-1000460-g004: Nlaz acts downstream of JNK to maintain metabolic homeostasis.(A) Percent of male flies surviving after being exposed to prolonged dry starvation. Populations are F1 progeny of crosses between hep1/FM6; pplG4/CyO females and OreR males (hep1/y; pplG4/+; n = 65) or w1118; UAS-NLaz/TM3 males (hep1/y; pplG4/UASNlaz; n = 70). Wild-type controls are F1 progeny of OreR females crossed to w1118 males (OreR/w1118; n = 181). p<0.001 (log rank test) for difference between hep1/y; ppl/+ and either of the other two populations. p = 0.629 (log rank test) for hep1/y; pplG4/UASNLaz compared to OreR/w1118. (B) Glucose and lipid content in homogenates prepared from populations of 10 male flies after 24 hours of wet starvation.

Mentions: These results suggested that JNK-mediated induction of NLaz in the fatbody regulates metabolic homeostasis. Supporting this view, we found that fatbody expression of NLaz was sufficient to restore starvation resistance and Glucose and Triglyceride levels in hep1 mutants (Figure 4). Fatbody-derived NLaz is likely to be secreted (see [34], and Figure S7), serving as systemic regulator of metabolic homeostasis. Supporting such a systemic role, we found that expression of NLaz in other tissues, such as pericardial cells and hemocytes of flies (using the dorothy-Gal4 driver, dot-Gal4 [45]), also protects against starvation (Figure S3B). A localized supply of NLaz is thus sufficient to exert its systemic protective function.


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)

Nlaz acts downstream of JNK to maintain metabolic homeostasis.(A) Percent of male flies surviving after being exposed to prolonged dry starvation. Populations are F1 progeny of crosses between hep1/FM6; pplG4/CyO females and OreR males (hep1/y; pplG4/+; n = 65) or w1118; UAS-NLaz/TM3 males (hep1/y; pplG4/UASNlaz; n = 70). Wild-type controls are F1 progeny of OreR females crossed to w1118 males (OreR/w1118; n = 181). p<0.001 (log rank test) for difference between hep1/y; ppl/+ and either of the other two populations. p = 0.629 (log rank test) for hep1/y; pplG4/UASNLaz compared to OreR/w1118. (B) Glucose and lipid content in homogenates prepared from populations of 10 male flies after 24 hours of wet starvation.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2667264&req=5

pgen-1000460-g004: Nlaz acts downstream of JNK to maintain metabolic homeostasis.(A) Percent of male flies surviving after being exposed to prolonged dry starvation. Populations are F1 progeny of crosses between hep1/FM6; pplG4/CyO females and OreR males (hep1/y; pplG4/+; n = 65) or w1118; UAS-NLaz/TM3 males (hep1/y; pplG4/UASNlaz; n = 70). Wild-type controls are F1 progeny of OreR females crossed to w1118 males (OreR/w1118; n = 181). p<0.001 (log rank test) for difference between hep1/y; ppl/+ and either of the other two populations. p = 0.629 (log rank test) for hep1/y; pplG4/UASNLaz compared to OreR/w1118. (B) Glucose and lipid content in homogenates prepared from populations of 10 male flies after 24 hours of wet starvation.
Mentions: These results suggested that JNK-mediated induction of NLaz in the fatbody regulates metabolic homeostasis. Supporting this view, we found that fatbody expression of NLaz was sufficient to restore starvation resistance and Glucose and Triglyceride levels in hep1 mutants (Figure 4). Fatbody-derived NLaz is likely to be secreted (see [34], and Figure S7), serving as systemic regulator of metabolic homeostasis. Supporting such a systemic role, we found that expression of NLaz in other tissues, such as pericardial cells and hemocytes of flies (using the dorothy-Gal4 driver, dot-Gal4 [45]), also protects against starvation (Figure S3B). A localized supply of NLaz is thus sufficient to exert its systemic protective function.

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