Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Laboratory of Chronobiology, Berlin, Germany.
Reseach Group Molecular Nutritional Medicine, Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
Diabetes. 2021 Sep;70(9):1985-1999. doi: 10.2337/db20-0910. Epub 2021 Jul 5.
Adipose tissue (AT) is a key metabolic organ which functions are rhythmically regulated by an endogenous circadian clock. Feeding is a "zeitgeber" aligning the clock in AT with the external time, but mechanisms of this regulation remain largely unclear. We tested the hypothesis that postprandial changes of the hormone insulin directly entrain circadian clocks in AT and investigated a transcriptional-dependent mechanism of this regulation. We analyzed gene expression in subcutaneous AT (SAT) of obese subjects collected before and after the hyperinsulinemic-euglycemic clamp or control saline infusion (SC). The expressions of core clock genes , and in SAT were differentially changed upon insulin and saline infusion, suggesting insulin-dependent clock regulation. In human stem cell-derived adipocytes, mouse 3T3-L1 cells, and AT explants from knockin mice, insulin induced a transient increase of the Per2 mRNA and protein expression, leading to the phase shift of circadian oscillations, with similar effects for Insulin effects were dependent on the region between -64 and -43 in the Per2 promoter but not on CRE and E-box elements. Our results demonstrate that insulin directly regulates circadian clocks in AT and isolated adipocytes, thus representing a primary mechanism of feeding-induced AT clock entrainment.
脂肪组织（AT）是一个关键的代谢器官，其功能受到内源性生物钟的节律调节。进食是一种“时间信号”，使 AT 中的时钟与外部时间同步，但这种调节的机制在很大程度上仍不清楚。我们检验了这样一个假设，即激素胰岛素餐后的变化可以直接使 AT 中的生物钟同步，并研究了这种调节的转录依赖性机制。我们分析了肥胖受试者在接受高胰岛素-正常血糖钳夹或对照生理盐水输注（SC）前后采集的皮下脂肪组织（SAT）中的基因表达。核心时钟基因 、 在 SAT 中的表达在胰岛素和生理盐水输注后发生了差异变化，表明胰岛素依赖性时钟调节。在人干细胞来源的脂肪细胞、小鼠 3T3-L1 细胞和来自 基因敲入小鼠的脂肪组织中，胰岛素诱导 Per2 mRNA 和蛋白表达的短暂增加，导致昼夜节律振荡的相位移动，具有类似的作用。胰岛素的作用依赖于 Per2 启动子中-64 到-43 之间的区域，但不依赖于 CRE 和 E-box 元件。我们的结果表明，胰岛素直接调节 AT 和分离的脂肪细胞中的生物钟，因此代表了进食诱导 AT 时钟同步的主要机制。
