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

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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. Metabolism of multicellular organisms has to adjust to environmental changes. Insulin signaling plays an important role in this regulation. Stress signals can repress Insulin signaling, curtailing growth to promote stress tolerance and extend lifespan. While this interaction allows managing energy resources under stress conditions, excessive JNK activity in adipose tissue of vertebrates has been found to promote type II diabetes. Thus, the interaction between stress and Insulin signaling has to be carefully regulated to ensure proper metabolic adaptation. Here, we identify a new regulatory mechanism by which stress signaling influences metabolism in fruitflies. We show that an evolutionarily conserved secreted protein, Neural Lazarillo (NLaz), is induced in response to stress signals, and that it is required for metabolic regulation. NLaz mutant animals are more sensitive to stress and show significant metabolic deficiencies. Similarly, increased expression of NLaz inhibits growth, but increases stress and starvation tolerance. We show that these functions are mediated by an interaction with the Insulin signaling pathway. Our results show that the regulation of NLaz by stress signals is critical for metabolic adaptation of the organism to environmental challenges. Both the Insulin and JNK signaling mechanisms analyzed here are evolutionarily conserved, suggesting that similar interactions control metabolic adaptation in vertebrates.

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