The circadian clock exerts temporal coordination of metabolic pathways. Clock disruption is intimately linked with the development of obesity and insulin resistance, and our previous studies found that the essential clock transcription activator, Brain and Muscle Arnt-like 1 (Bmal1), is a key regulator of adipogenesis. However, the metabolic consequences of chronic shiftwork on adipose tissues have not been clearly defined. Here, using an environmental lighting-induced clock disruption that mimics rotating shiftwork schedule, we show that chronic clock dysregulation for 6 months in mice resulted in striking adipocyte hypertrophy with adipose tissue inflammation and fibrosis. Both visceral and subcutaneous depots display enlarged adipocyte with prominent crown-like structures indicative of macrophage infiltration together with evidence of extracellular matrix remodeling. Global transcriptomic analyses of these fat depots revealed that shiftwork resulted in up-regulations of inflammatory, adipogenic and angiogenic pathways with disruption of normal time-of-the-day-dependent regulation. These changes in adipose tissues are associated with impaired insulin signaling in mice subjected to shiftwork, together with suppression of the mTOR signaling pathway. Taken together, our study identified the significant adipose depot dysfunctions induced by chronic shiftwork regimen that may underlie the link between circadian misalignment and insulin resistance.

生物钟发挥代谢途径的时间协调作用。时钟中断与肥胖和胰岛素抵抗的发展密切相关，我们之前的研究发现，必需的时钟转录激活因子 Brain and Muscle Arnt-like 1 (Bmal1) 是脂肪生成的关键调节因子。然而，长期轮班对脂肪组织的代谢后果尚未明确定义。在这里，我们使用模拟轮班工作时间表的环境照明诱导的时钟中断，表明小鼠慢性时钟失调 6 个月导致脂肪细胞肥大，伴有脂肪组织炎症和纤维化。内脏和皮下贮库均显示增大的脂肪细胞，具有突出的冠状结构，表明巨噬细胞浸润以及细胞外基质重塑的证据。对这些脂肪库的全球转录组学分析表明，轮班工作导致炎症、脂肪生成和血管生成通路的上调，同时破坏了正常的一天中时间依赖性调节。脂肪组织的这些变化与轮班工作小鼠的胰岛素信号传导受损以及 mTOR 信号通路的抑制有关。总之，我们的研究确定了由慢性轮班工作方案引起的显着脂肪库功能障碍，这可能是昼夜节律失调与胰岛素抵抗之间联系的基础。对这些脂肪库的全球转录组学分析表明，轮班工作导致炎症、脂肪生成和血管生成通路的上调，同时破坏了正常的一天中时间依赖性调节。脂肪组织的这些变化与轮班工作小鼠的胰岛素信号传导受损以及 mTOR 信号通路的抑制有关。总之，我们的研究确定了由慢性轮班工作方案引起的显着脂肪库功能障碍，这可能是昼夜节律失调与胰岛素抵抗之间联系的基础。对这些脂肪库的全球转录组学分析表明，轮班工作导致炎症、脂肪生成和血管生成通路的上调，同时破坏了正常的一天中时间依赖性调节。脂肪组织的这些变化与轮班工作小鼠的胰岛素信号传导受损以及 mTOR 信号通路的抑制有关。总之，我们的研究确定了由慢性轮班工作方案引起的显着脂肪库功能障碍，这可能是昼夜节律失调与胰岛素抵抗之间联系的基础。脂肪组织的这些变化与轮班工作小鼠的胰岛素信号传导受损以及 mTOR 信号通路的抑制有关。总之，我们的研究确定了由慢性轮班工作方案引起的显着脂肪库功能障碍，这可能是昼夜节律失调与胰岛素抵抗之间联系的基础。脂肪组织的这些变化与轮班工作小鼠的胰岛素信号传导受损以及 mTOR 信号通路的抑制有关。总之，我们的研究确定了由慢性轮班工作方案引起的显着脂肪库功能障碍，这可能是昼夜节律失调与胰岛素抵抗之间联系的基础。