Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz.
Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz.
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DOI：
10.1371/journal.pgen.1000460
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发表时间：
2009-04
期刊：
影响因子：
4.5
通讯作者：
Jasper H
中科院分区：
文献类型：
--
作者：
Hull-Thompson J;Muffat J;Sanchez D;Walker DW;Benzer S;Ganfornina MD;Jasper H
后生动物的代谢稳态是通过内分泌控制胰岛素/IGF信号（IIS）活性来调节的。应激和炎症信号通路-如jun - n-末端激酶（JNK）信号通路-抑制IIS，减少合成代谢过程以促进应激耐受性和延长寿命。虽然这种相互作用构成了一种适应性反应，允许在压力条件下管理能量资源，但脊椎动物脂肪组织中过量的JNK活性已被发现导致胰岛素抵抗，促进II型糖尿病。因此，JNK和IIS之间的相互作用必须受到严格调节，以确保适当的代谢适应环境挑战。在这里，我们确定了JNK影响代谢系统的一种新的调节机制。我们发现JNK信号是果蝇代谢稳态所必需的，而这一功能是由果蝇脂钙蛋白家族成员神经Lazarillo （NLaz）介导的，它是脊椎动物载脂蛋白D （ApoD）和视黄醇结合蛋白4 （RBP4）的同源物。脂载蛋白作为外周胰岛素敏感性的中枢调节因子出现，并与代谢疾病有关。NLaz受JNK信号的转录调控，是JNK介导的应激和饥饿耐受所必需的。NLaz功能的丧失会降低抗逆性和寿命，而其过表达会抑制生长，促进抗逆性和延长寿命，这些表型与IIS活性降低一致。因此，我们发现NLaz在幼虫和成虫中抑制IIS活性。我们的研究结果表明，JNK-NLaz信号可以拮抗IIS，并且对于生物体对环境挑战的代谢适应至关重要。JNK通路和脂钙素在结构和功能上都是保守的，这表明类似的相互作用代表了一个控制代谢稳态的进化保守系统。多细胞生物的新陈代谢必须适应环境的变化。胰岛素信号在这一调节中起着重要作用。应激信号可以抑制胰岛素信号，抑制生长以促进应激耐受性和延长寿命。虽然这种相互作用允许在压力条件下管理能量资源，但脊椎动物脂肪组织中过量的JNK活性已被发现可促进II型糖尿病。因此，应激和胰岛素信号之间的相互作用必须仔细调节，以确保适当的代谢适应。在这里，我们确定了应激信号影响果蝇代谢的一种新的调节机制。我们发现一种进化上保守的分泌蛋白Neural Lazarillo （NLaz）在应激信号下被诱导，并且它是代谢调节所必需的。NLaz突变动物对压力更敏感，并表现出明显的代谢缺陷。同样，NLaz表达的增加抑制了生长，但增加了对胁迫和饥饿的耐受性。我们发现这些功能是通过与胰岛素信号通路的相互作用介导的。我们的研究结果表明，胁迫信号对NLaz的调节对于生物体对环境挑战的代谢适应至关重要。这里分析的胰岛素和JNK信号机制都是进化保守的，这表明类似的相互作用控制着脊椎动物的代谢适应。
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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影响因子：
64.5
作者：
Böhni, R;Riesgo-Escovar, J;Hafen, E
通讯作者：
Hafen, E
影响因子：
64.8
作者：
Kahn, Steven E.;Hull, Rebecca L.;Utzschneider, Kristina M.
通讯作者：
Utzschneider, Kristina M.
影响因子：
4.6
作者：
Gershman, Boris;Puig, Oscar;Garofalo, Robert S.
通讯作者：
Garofalo, Robert S.
影响因子：
158.5
作者：
Graham, Timothy E.;Yang, Qin;Kahn, Barbara B.
通讯作者：
Kahn, Barbara B.
DOI：
10.1073/pnas.0405775102
发表时间：
2005-02-22
影响因子：
11.1
作者：
Broughton, SJ;Piper, MDW;Partridge, L
通讯作者：
Partridge, L