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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 is required for maintenance of metabolic homeostasis.(A–E) Comparison of hemizygous hep1 males (hep1/y) to wild type OreR males. (A–C) Carbohydrate and lipid content in homogenates prepared from populations of 10 flies prior to and after 6, 24, and 30 hours of wet starvation. All measurements were normalized to the average weight of a single fly in its population. (A) Glucose. (B) Glycogen. (C) Triglycerides. (D) Real time PCR results from cDNA prepared from starved adult males collected 6, 24, and 30 hours after wet starvation. Levels of PEPCK are compared in starved conditions to fed controls (0 hours). All transcripts are normalized to actin5C. (E,F) Percent of male flies surviving after prolonged dry starvation. Population sizes were (E) OreR: n = 151; hep1: n = 103. Lifespan differences are statistically significant (p<0.001, log rank test). (F) DaG4/+: n = 179; BskRNAi/+;DaG4/+: n = 138. p<0.001, log rank test. (F, inset) Real time PCR on cDNA prepared from BskRNAi/+;DaG4/+ larvae. Levels of Bsk are compared to DAG4/+ controls. All transcripts are normalized to rp49.
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pgen-1000460-g001: JNK is required for maintenance of metabolic homeostasis.(A–E) Comparison of hemizygous hep1 males (hep1/y) to wild type OreR males. (A–C) Carbohydrate and lipid content in homogenates prepared from populations of 10 flies prior to and after 6, 24, and 30 hours of wet starvation. All measurements were normalized to the average weight of a single fly in its population. (A) Glucose. (B) Glycogen. (C) Triglycerides. (D) Real time PCR results from cDNA prepared from starved adult males collected 6, 24, and 30 hours after wet starvation. Levels of PEPCK are compared in starved conditions to fed controls (0 hours). All transcripts are normalized to actin5C. (E,F) Percent of male flies surviving after prolonged dry starvation. Population sizes were (E) OreR: n = 151; hep1: n = 103. Lifespan differences are statistically significant (p<0.001, log rank test). (F) DaG4/+: n = 179; BskRNAi/+;DaG4/+: n = 138. p<0.001, log rank test. (F, inset) Real time PCR on cDNA prepared from BskRNAi/+;DaG4/+ larvae. Levels of Bsk are compared to DAG4/+ controls. All transcripts are normalized to rp49.

Mentions: Based on the ability of JNK signaling to antagonize IIS activity in flies and worms [4],[10], and on the starvation tolerance of flies with increased JNK signaling activity [35], we hypothesized that this pathway plays a role in regulating metabolic homeostasis under physiological conditions. To start characterizing such a role, we analyzed the maintenance of nutrient stores under starvation conditions in wild-type flies and in flies mutant for the JNK activating Kinase Hemipterous (JNKK/Hep). Interestingly, males hemizygous for the hep loss-of-function allele hep1 exhibited significantly reduced energy stores (lipids and carbohydrates) in ad libitum conditions compared to wild-type control flies, suggesting impaired metabolic homeostasis in these animals (Figure 1A–C, Figure S1A). Accordingly, we found that in hep1 mutants, nutrient stores were rapidly depleted upon starvation. Interestingly, hep1 mutants also exhibited an accelerated and increased gluconeogenic response to starvation (Figure 1D), measured by phosphoenolpyruvate carboxykinase (PEPCK) expression [36], supporting the idea that JNK signaling mutants suffer a rapid decline in available free sugars upon starvation. Consistent with this view, hep1 hemizygotes are significantly more sensitive to starvation than wild-type controls (Figures 1E and Figure S1B). Similarly, flies in which JNK signaling was repressed by ubiquitous over-expression of a dsRNA against the Drosophila JNK Basket (Bsk) were sensitive to starvation, confirming a loss of metabolic homeostasis in JNK loss-of-function conditions (Figure 1F and Figure S1C).


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 is required for maintenance of metabolic homeostasis.(A–E) Comparison of hemizygous hep1 males (hep1/y) to wild type OreR males. (A–C) Carbohydrate and lipid content in homogenates prepared from populations of 10 flies prior to and after 6, 24, and 30 hours of wet starvation. All measurements were normalized to the average weight of a single fly in its population. (A) Glucose. (B) Glycogen. (C) Triglycerides. (D) Real time PCR results from cDNA prepared from starved adult males collected 6, 24, and 30 hours after wet starvation. Levels of PEPCK are compared in starved conditions to fed controls (0 hours). All transcripts are normalized to actin5C. (E,F) Percent of male flies surviving after prolonged dry starvation. Population sizes were (E) OreR: n = 151; hep1: n = 103. Lifespan differences are statistically significant (p<0.001, log rank test). (F) DaG4/+: n = 179; BskRNAi/+;DaG4/+: n = 138. p<0.001, log rank test. (F, inset) Real time PCR on cDNA prepared from BskRNAi/+;DaG4/+ larvae. Levels of Bsk are compared to DAG4/+ controls. All transcripts are normalized to rp49.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2667264&req=5

pgen-1000460-g001: JNK is required for maintenance of metabolic homeostasis.(A–E) Comparison of hemizygous hep1 males (hep1/y) to wild type OreR males. (A–C) Carbohydrate and lipid content in homogenates prepared from populations of 10 flies prior to and after 6, 24, and 30 hours of wet starvation. All measurements were normalized to the average weight of a single fly in its population. (A) Glucose. (B) Glycogen. (C) Triglycerides. (D) Real time PCR results from cDNA prepared from starved adult males collected 6, 24, and 30 hours after wet starvation. Levels of PEPCK are compared in starved conditions to fed controls (0 hours). All transcripts are normalized to actin5C. (E,F) Percent of male flies surviving after prolonged dry starvation. Population sizes were (E) OreR: n = 151; hep1: n = 103. Lifespan differences are statistically significant (p<0.001, log rank test). (F) DaG4/+: n = 179; BskRNAi/+;DaG4/+: n = 138. p<0.001, log rank test. (F, inset) Real time PCR on cDNA prepared from BskRNAi/+;DaG4/+ larvae. Levels of Bsk are compared to DAG4/+ controls. All transcripts are normalized to rp49.
Mentions: Based on the ability of JNK signaling to antagonize IIS activity in flies and worms [4],[10], and on the starvation tolerance of flies with increased JNK signaling activity [35], we hypothesized that this pathway plays a role in regulating metabolic homeostasis under physiological conditions. To start characterizing such a role, we analyzed the maintenance of nutrient stores under starvation conditions in wild-type flies and in flies mutant for the JNK activating Kinase Hemipterous (JNKK/Hep). Interestingly, males hemizygous for the hep loss-of-function allele hep1 exhibited significantly reduced energy stores (lipids and carbohydrates) in ad libitum conditions compared to wild-type control flies, suggesting impaired metabolic homeostasis in these animals (Figure 1A–C, Figure S1A). Accordingly, we found that in hep1 mutants, nutrient stores were rapidly depleted upon starvation. Interestingly, hep1 mutants also exhibited an accelerated and increased gluconeogenic response to starvation (Figure 1D), measured by phosphoenolpyruvate carboxykinase (PEPCK) expression [36], supporting the idea that JNK signaling mutants suffer a rapid decline in available free sugars upon starvation. Consistent with this view, hep1 hemizygotes are significantly more sensitive to starvation than wild-type controls (Figures 1E and Figure S1B). Similarly, flies in which JNK signaling was repressed by ubiquitous over-expression of a dsRNA against the Drosophila JNK Basket (Bsk) were sensitive to starvation, confirming a loss of metabolic homeostasis in JNK loss-of-function conditions (Figure 1F and Figure S1C).

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