Interplay of peripheral circadian clocks with energy balance and body weight regulation

生理时钟——存在于下丘脑和外周组织中的内源性振荡器——和代谢过程紧密地交织在一起：大量证据表明，一个系统的失调会严重影响另一个系统，反之亦然。然而，关于(1)进餐时间的作用以及(2)组织特异性生物钟在体重调节中的作用，我们所知甚少。在第一个资助期，我们可以证明胰岛素直接调节小鼠和人类脂肪组织以及小鼠肝细胞中时钟基因Per2的表达。这些发现提供了与能量代谢的直接联系，因为Per2被证明可以调节小鼠的昼夜食物摄入、激素节律（糖皮质激素和α - hamsh）和肥胖。人类单核细胞显示出与脂肪组织相似的昼夜节律模式。人的膳食试验显示PER2在人体内有急性调节。此外，降低食物中的碳水化合物含量导致人体生物钟基因PER1、PER2、PER3和DBP的昼夜节律基因表达明显改变，这与许多与能量代谢相关的代谢和炎症基因表达改变有关。因此，我们建议研究昼夜节律系统与食物摄入在能量失衡（如肥胖）管理中的相互作用。具体来说，我们将研究脂肪组织和肝脏生物钟在小鼠体重调节中的作用，使用适当的遗传模型和喂养模式。此外，还将分析胰岛素信号在细胞水平上影响生物钟基因表达的机制，并可能导致摄食诱导的生物钟干扰。一项人体研究旨在揭示昼夜节律机制与代谢/激素对食物摄入的反应之间的相互作用。为此，将研究白天食物诱导对生物钟基因表达和胰岛素反应的依赖性，以及它们对生物钟基因和激素/代谢反应的相互调节，从而将动物数据转化为人类应用。

Circadian clocks - endogenous oscillators present in the hypothalamus as well as in peripheral tissues - and metabolic processes are intimately intertwined: a huge body of evidence demonstrates that dysregulation of one system substantially affects the other and vice versa. Little is known, however, about (i) the role of meal timing as well as (ii) the role of tissue-specific circadian clocks for body weight (BW) regulation. In the first funding period we could show that insulin directly regulates the expression of the clock gene Per2 in mouse and human adipose tissue as well as in murine hepatocytes. These findings provide a direct link to energy metabolism since Per2 was shown to regulate circadian food intake, hormonal rhythms (glucocorticoids and alphaMSH) and obesity in mice. Human monocytes were shown to display similar circadian patterns as adipose tissue. Meal tests in humans showed acute regulation of PER2 in man. Moreover, lowering the carbohydrate content of foods resulted in a pronounced shift of circadian gene expression of the clock genes PER1, PER2, PER3 and of DBP in man which was associated with an altered expression of numerous metabolic and inflammatory genes related to energy metabolism. We therefore propose to investigate the interaction of the circadian system with food intake in the management of energy imbalance such as obesity. Specifically, we will study the role of adipose tissue and liver circadian clocks in mice for body weight regulation using appropriate genetic models and feeding paradigms. In addition, the mechanisms by which insulin signaling affects clock gene expression at a cellular level and potentially contributes to feeding-induced entrainment of circadian clocks will be analyzed. Complementary a human study aims to unravel the interaction of circadian mechanisms with metabolic/hormonal responses to food intake. To this end, the daytime dependence of food-induced effects on clock gene expression as well as on insulin responses will be examined with regard to their reciprocal regulation of clock genes and hormonal / metabolic responses thereby translating the animal data into human application.