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Control of Metabolic Homeostasis by Stress Signaling Is Mediated by the Lipocalin NLaz
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 thi...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667264/ https://www.ncbi.nlm.nih.gov/pubmed/19390610 http://dx.doi.org/10.1371/journal.pgen.1000460 |
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author | Hull-Thompson, Julie Muffat, Julien Sanchez, Diego Walker, David W. Benzer, Seymour Ganfornina, Maria D. Jasper, Heinrich |
author_facet | Hull-Thompson, Julie Muffat, Julien Sanchez, Diego Walker, David W. Benzer, Seymour Ganfornina, Maria D. Jasper, Heinrich |
author_sort | Hull-Thompson, Julie |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2667264 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-26672642009-04-24 Control of Metabolic Homeostasis by Stress Signaling Is Mediated by the Lipocalin NLaz Hull-Thompson, Julie Muffat, Julien Sanchez, Diego Walker, David W. Benzer, Seymour Ganfornina, Maria D. Jasper, Heinrich PLoS Genet Research Article 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. Public Library of Science 2009-04-24 /pmc/articles/PMC2667264/ /pubmed/19390610 http://dx.doi.org/10.1371/journal.pgen.1000460 Text en Hull-Thompson et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Hull-Thompson, Julie Muffat, Julien Sanchez, Diego Walker, David W. Benzer, Seymour Ganfornina, Maria D. Jasper, Heinrich Control of Metabolic Homeostasis by Stress Signaling Is Mediated by the Lipocalin NLaz |
title | Control of Metabolic Homeostasis by Stress Signaling Is Mediated by the Lipocalin NLaz |
title_full | Control of Metabolic Homeostasis by Stress Signaling Is Mediated by the Lipocalin NLaz |
title_fullStr | Control of Metabolic Homeostasis by Stress Signaling Is Mediated by the Lipocalin NLaz |
title_full_unstemmed | Control of Metabolic Homeostasis by Stress Signaling Is Mediated by the Lipocalin NLaz |
title_short | Control of Metabolic Homeostasis by Stress Signaling Is Mediated by the Lipocalin NLaz |
title_sort | control of metabolic homeostasis by stress signaling is mediated by the lipocalin nlaz |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667264/ https://www.ncbi.nlm.nih.gov/pubmed/19390610 http://dx.doi.org/10.1371/journal.pgen.1000460 |
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