Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published April 24, 2009 | Published
Journal Article Open

Control of Metabolic Homeostasis by Stress Signaling Is Mediated by the Lipocalin NLaz

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.

Additional Information

© 2009 Hull-Thompson et al. 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 credited. This work was supported by NIH grant RO1 AG028127 to HJ, MEC grant BFU2005-00522 and JCyL grant VA049A05 to MDG and DS, and Muscular Dystrophy Association development grant (to DWW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. We thank Benoit Biteau and Jason Karpac for comments on the manuscript, Olga Dunaevsky and Judith Acebes for technical assistance, and Dirk Bohmann for helpful discussions. Author Contributions: Conceived and designed the experiments: JHT JM SB MDG HJ. Performed the experiments: JHT JM DS MDG HJ. Analyzed the data: JHT JM DS DWW MDG HJ. Contributed reagents/materials/analysis tools: DWW SB MDG. Wrote the paper: JHT HJ.

Attached Files

Published - HullThompson2009p4461Plos_Genet.pdf

Files

HullThompson2009p4461Plos_Genet.pdf
Files (2.3 MB)
Name Size Download all
md5:ff7940040ac54be0a3b1f057a4bc1fe5
2.3 MB Preview Download

Additional details

Created:
August 20, 2023
Modified:
October 18, 2023