Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148.
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148
Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9491-6. doi: 10.1073/pnas.1409427111. Epub 2014 Jun 16.
Obesity develops in response to an imbalance of energy homeostasis and whole-body metabolism. Muscle plays a central role in the control of energy homeostasis through consumption of energy and signaling to adipose tissue. We reported previously that MED13, a subunit of the Mediator complex, acts in the heart to control obesity in mice. To further explore the generality and mechanistic basis of this observation, we investigated the potential influence of MED13 expression in heart and muscle on the susceptibility of Drosophila to obesity. Here, we show that heart/muscle-specific knockdown of MED13 or MED12, another Mediator subunit, increases susceptibility to obesity in adult flies. To identify possible muscle-secreted obesity regulators, we performed an RNAi-based genetic screen of 150 genes that encode secreted proteins and found that Wingless inhibition also caused obesity. Consistent with these findings, muscle-specific inhibition of Armadillo, the downstream transcriptional effector of the Wingless pathway, also evoked an obese phenotype in flies. Epistasis experiments further demonstrated that Wingless functions downstream of MED13 within a muscle-regulatory pathway. Together, these findings reveal an intertissue signaling system in which Wingless acts as an effector of MED13 in heart and muscle and suggest that Wingless-mediated cross-talk between striated muscle and adipose tissue controls obesity in Drosophila. This signaling system appears to represent an ancestral mechanism for the control of systemic energy homeostasis.
肥胖是由于能量平衡和全身代谢失衡而发展的。肌肉通过消耗能量和向脂肪组织发出信号，在能量平衡的控制中起着核心作用。我们之前报道过，中介复合物的一个亚基 MED13 在心脏中发挥作用，控制小鼠的肥胖。为了进一步探索这一观察结果的普遍性和机制基础，我们研究了 MED13 在心脏和肌肉中的表达对果蝇肥胖易感性的潜在影响。在这里，我们表明，心脏/肌肉特异性敲低 MED13 或 MED12（另一个中介亚基）会增加成年果蝇肥胖的易感性。为了鉴定可能的肌肉分泌性肥胖调节剂，我们对编码分泌蛋白的 150 个基因进行了基于 RNAi 的遗传筛选，发现 Wingless 抑制也会导致肥胖。这些发现一致表明，Wingless 途径的下游转录效应因子 Armadillo 在肌肉中的特异性抑制也会在果蝇中引起肥胖表型。上位性实验进一步表明，Wingless 在肌肉调节途径中位于 MED13 下游。总之，这些发现揭示了一个组织间信号系统，其中 Wingless 作为心脏和肌肉中 MED13 的效应物发挥作用，并表明 Wingless 介导的横纹肌和脂肪组织之间的串扰控制果蝇肥胖。这种信号系统似乎代表了控制全身能量平衡的古老机制。
