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

项目总结 昼夜节律紊乱与肥胖和代谢性疾病密切相关。带有A的小鼠 时钟失调和经历倒班工作、时差和睡眠障碍的人会患上血糖 不耐受、胰岛素抵抗和体重增加。最近的数据表明，食物消费的时机是一个关键 新陈代谢健康的决定因素。在持续的黑暗中，老鼠和人类的昼夜节律被打乱 饮食诱导生热(DIT)。此外，我们的实验室发现，在小鼠的饮食过程中，等卡路里的摄入 与黑暗时期相比，光明时期会导致明显的体重增加和葡萄糖耐量减低。这 在缺乏脂肪组织的小鼠中，光明和黑暗时期不同体重增加的影响消失 生热作用。这表明脂肪组织产热是以昼夜节律的方式调节的，以对齐DIT 有最佳的摄食时间(小鼠的暗期)。然而，整合脂肪组织的机制 摄食的生热作用尚不清楚。在这项提案中，我们的目标是描述中央昼夜节律 控制脂肪组织的交感神经刺激和生热激活。这项提案中的实验 将揭示一种新的神经回路，它使摄食节奏与脂肪组织DIT保持一致，以保持能量 动态平衡。

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.