Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptive and -maladaptive response to various chronic stresses. Here, we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER-stressed “donor” cells resulted in intercellular transmission of ERS and dysfunction to ERS-naive “recipient” cells (“bystander response”), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism.

内质网应激 (ERS) 在肥胖相关的胰岛素抵抗中具有病理生理学作用。然而，协调组织对 ERS ​​的反应仍不清楚。增加的连接蛋白 43 (Cx43) 介导的细胞间通讯与对各种慢性应激的组织适应和适应不良反应有关。在这里，我们证明在肝细胞中，ERS 导致 Cx43 表达和细胞-细胞耦合增加。ER 应激的“供体”细胞的共培养导致 ERS ​​的细胞间传递和对 ERS ​​幼稚“受体”细胞的功能障碍（“旁观者反应”），这可以通过 Cx43 的遗传或药理学抑制来预防。肥胖小鼠的肝细胞能够将 ERS ​​传递给瘦小鼠的肝细胞，缺乏肝脏 Cx43 的小鼠可以免受饮食诱导的 ERS、胰岛素抵抗和肝脂肪变性的影响。总之，我们的结果表明，在肥胖症中，增加的 Cx43 介导的细胞-细胞耦合允许 ERS ​​的细胞间传播。这种对过度营养的新适应不良反应加剧了组织 ERS ​​负担，促进肝脂肪变性并损害全身葡萄糖代谢。