Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.
Genes Dev. 2018 Jan 15;32(2):156-164. doi: 10.1101/gad.305870.117. Epub 2018 Feb 9.
Insulin resistance, the failure to activate insulin signaling in the presence of ligand, leads to metabolic diseases, including type 2 diabetes. Physical activity and mechanical stress have been shown to protect against insulin resistance, but the molecular mechanisms remain unclear. Here, we address this relationship in the larval fat body, an insulin-sensitive organ analogous to vertebrate adipose tissue and livers. We found that insulin signaling in fat body cells is abolished in the absence of physical activity and mechanical stress even when excess insulin is present. Physical movement is required for insulin sensitivity in both intact larvae and fat bodies cultured ex vivo. Interestingly, the insulin receptor and other downstream components are recruited to the plasma membrane in response to mechanical stress, and this membrane localization is rapidly lost upon disruption of larval or tissue movement. Sensing of mechanical stimuli is mediated in part by integrins, whose activation is necessary and sufficient for mechanical stress-dependent insulin signaling. Insulin resistance develops naturally during the transition from the active larval stage to the immotile pupal stage, suggesting that regulation of insulin sensitivity by mechanical stress may help coordinate developmental programming with metabolism.
胰岛素抵抗是指在配体存在的情况下，胰岛素信号无法被激活，从而导致代谢疾病，包括 2 型糖尿病。已经有研究表明，身体活动和机械应激可以预防胰岛素抵抗，但其中的分子机制尚不清楚。在这里，我们在幼虫脂肪体中研究了这种关系，脂肪体是一种对胰岛素敏感的器官，类似于脊椎动物的脂肪组织和肝脏。我们发现，即使存在过量的胰岛素，在没有身体活动和机械应激的情况下，脂肪体细胞中的胰岛素信号也会被完全阻断。完整幼虫和离体培养的脂肪体都需要进行身体运动才能保持胰岛素敏感性。有趣的是，胰岛素受体和其他下游成分在机械应激的作用下被募集到质膜上，而当幼虫或组织运动被破坏时，这种质膜定位会迅速丢失。机械刺激的感知部分是由整合素介导的，其激活对于机械应激依赖的胰岛素信号传导是必要和充分的。胰岛素抵抗在从活跃的幼虫阶段到不活动的蛹阶段的过渡过程中自然发生，这表明机械应激对胰岛素敏感性的调节可能有助于协调代谢与发育编程。
