A Central Circadian Clock-Adipose Tissue Circuit Regulates Thermogenesis and Energy Balance

项目摘要 昼夜节律的破坏与肥胖和代谢疾病密切相关。的小鼠 生物钟功能失调和经历轮班工作、时差反应和睡眠障碍的人会产生葡萄糖 不耐受、胰岛素抵抗和体重增加。最近的数据表明，食物消费的时间是一个关键 代谢健康的决定因素。处于持续黑暗中的小鼠和人类的昼夜节律被打乱， 饮食诱导产热（DIT）。此外，我们的实验室已经发现，在小鼠中进行等热量喂养， 与黑暗期相比，光照期导致明显的体重增加和葡萄糖耐受不良。这 在缺乏脂肪组织的小鼠中，在光与暗期间差异性体重增加的效果消失 产热作用这表明脂肪组织产热是以昼夜节律的方式调节的， 最佳喂养时间（小鼠的黑暗期）。然而，整合脂肪组织的机制 与摄食有关的产热作用仍不清楚。在这个建议中，我们的目标是描述中央昼夜节律， 控制脂肪组织交感神经刺激和产热激活。该提案中的实验 将揭示一种新的神经回路，使进食节奏与脂肪组织DIT保持一致， 体内平衡

PROJECT SUMMARY Disruption of circadian rhythms is strongly correlated to obesity and metabolic diseases. Mice with a dysfunctional clock and individuals who experience shift work, jet lag, and sleep disorders develop glucose intolerance, insulin resistance, and weight gain. Recent data indicates the timing of food consumption is a key determinant of metabolic health. Mice and humans in constant darkness have a disrupted diurnal rhythm of diet-induced thermogenesis (DIT). Furthermore, our lab has found that isocaloric feeding in mice during the light period results in pronounced weight gain and glucose intolerance, as compared to the dark period. This effect of differential weight gain during the light vs dark period is lost in mice lacking adipose tissue thermogenesis. This suggests adipose tissue thermogenesis is regulated in a circadian manner to align DIT with optimal feeding times (dark period in mice). However, the mechanisms that integrate adipose tissue thermogenesis with feeding remain unclear. In this proposal, we aim to characterize the central circadian control of adipose tissue sympathetic stimulation and thermogenic activation. The experiments in this proposal will reveal a novel neurocircuit that aligns feeding rhythms with adipose tissue DIT to maintain energy homeostasis.