Interplay of peripheral clock genes with energy balance and nutrients: Role of hormonal pathways

生物钟是内源性振荡器，存在于下丘脑和外周组织中，调节生理、新陈代谢和行为的日常节奏。生物钟的基本机制是细胞自主的：时钟基因和蛋白质形成调节网络，在分子水平上产生节奏。它们的缺失不仅会导致生物钟功能障碍，还会导致肥胖和代谢功能障碍。时钟基因调节内分泌节律、体重和温度、脂肪代谢和脂肪细胞分化、异体代谢等过程。另一方面，代谢信号本身调节脂肪组织、肝脏和肠道的时钟基因表达，例如进餐时间，特别是在能量限制的情况下。我们最近发现INTIN GIP是一种新的信号，调节人类时钟基因的表达。我们的子项目的目标是在人类、动物模型和组织培养细胞中将时钟基因的表达和功能与激素和代谢调节联系起来。由于动物体内Clock基因的表达受热量限制的影响很大，因此我们在Z项目中特别关注能量限制和随后的体重维持/恢复的条件。此外，我们还将测试进餐时间对外周血单核细胞和脂肪组织中人类时钟基因表达的影响。在动物模型中，我们将利用GIP治疗和GIP受体缺陷小鼠来研究(I)GIP在食物诱导的昼夜节律中的特定作用，以及(Ii)饮食诱导的肥胖对相关外周组织的生物钟特性的影响。此外，我们将使用昼夜荧光素酶报告系统以及基因表达研究来表征脂肪细胞组织培养细胞中胰岛素和食欲调节激素对时钟基因的调控。我们的实验将显示时钟基因的表达/功能是否与热量限制相关并被热量限制改变，并参与体重恢复的反向调节。我们将尝试识别相关的荷尔蒙线索，并根据时钟基因的调节制定体重维持策略。

Circadian clocks are endogenous oscillators, present in the hypothalamus as well as in peripheral tissues that regulate daily rhythms in physiology, metabolism and behavior. The fundamental mechanism of circadian clocks is cell-autonomous: clock genes and proteins form regulatory networks that generate rhythms on the molecular level. Their deletion not only leads to clock dysfunction but also to obesity and metabolic dysfunction. Clock genes modulate endocrine rhythms, body weight and temperature, fat metabolism and fat cell differentiation, xenobiotic metabolism, amongst other processes. On the other hand, metabolic cues - such as meal timing particularly under conditions of energy restriction – themselves regulate clock gene expression in adipose tissue, liver and intestine. We recently identified the incretin GIP as a novel cue modulating clock gene expression in humans. Our subproject’s aim is to correlate clock gene expression and function to hormonal and metabolic regulation in humans, animal models and tissue culture cells. Since clock gene expression is substantially altered by caloric restriction in animals, we particularly focus on conditions of energy restriction and subsequent weight maintenance/regain in the Z project. In addition, we will test meal timing for effects on human clock gene expression in PBMCs and adipose tissue. In animal models we will characterize (i) the specific role of GIP on food entrained circadian rhythms using GIP treatment and GIP-receptor deficient mice and (ii) the effect of diet-induced obesity on circadian clock properties in relevant peripheral tissues. Moreover we will characterize clock gene regulation by incretins and appetite regulating hormones in adipocyte tissue culture cells using a circadian luciferase reporter system as well as gene expression studies. Our experiments will show whether clock gene expression/function is correlated with and altered by caloric restriction and involved in the counter-regulation of weight regain. We will attempt to identify hormonal cues involved and develop strategies for weight maintenance based on the regulation of clock genes.