Systemic Activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila melanogaster
Systemic Activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila melanogaster
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DOI：
10.1073/pnas.1319116111
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发表时间：
2014-04-15
影响因子：
11.1
通讯作者：
O'Connor, Michael B.
中科院分区：
文献类型：
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作者：
Ghosh, Arpan C.;O'Connor, Michael B.
维持细胞和生理代谢稳态的能力是多细胞生物在不断变化的环境条件下生存的关键。然而，我们对调节代谢过程的细胞外信号通路的理解仍然有限。在这项研究中，我们发现激活素样配体 Dawdle (Daw) 是果蝇全身代谢稳态和细胞代谢的主要调节因子。我们发现 Daw 下游经典 Smad 信号传导的丧失会导致糖和全身 pH 稳态的缺陷。尽管 Daw 通过积极影响胰岛素释放来调节糖稳态，但我们发现 Daw 对 pH 平衡的影响与其在胰岛素信号传导中的作用无关，并且是由主要是三羧酸 (TCA) 循环中间体的有机酸的积累引起的。 RNA测序显示，许多TCA循环酶和核编码线粒体基因（包括参与氧化磷酸化和β-氧化的基因）在daw突变体中上调，表明Daw在调节这些基因中具有直接或间接作用。这些发现确立了激活素信号传导作为主要的代谢调节剂，并揭示了果蝇中 TGF-β 信号传导、胰岛素信号传导和代谢之间的功能联系。
The ability to maintain cellular and physiological metabolic homeostasis is key for the survival of multicellular organisms in changing environmental conditions. However, our understanding of extracellular signaling pathways that modulate metabolic processes remains limited. In this study we show that the Activin-like ligand Dawdle (Daw) is a major regulator of systemic metabolic homeostasis and cellular metabolism in Drosophila. We find that loss of canonical Smad signaling downstream of Daw leads to defects in sugar and systemic pH homeostasis. Although Daw regulates sugar homeostasis by positively influencing insulin release, we find that the effect of Daw on pH balance is independent of its role in insulin signaling and is caused by accumulation of organic acids that are primarily tricarboxylic acid (TCA) cycle intermediates. RNA sequencing reveals that a number of TCA cycle enzymes and nuclear-encoded mitochondrial genes including genes involved in oxidative phosphorylation and beta-oxidation are up-regulated in the daw mutants, indicating either a direct or indirect role of Daw in regulating these genes. These findings establish Activin signaling as a major metabolic regulator and uncover a functional link between TGF-beta signaling, insulin signaling, and metabolism in Drosophila.