Hormonal Regulation of Energy Expenditure in Mice

我们NSERC发现研究计划的目标是了解哺乳动物能量代谢的调节。棕色脂肪组织(BAT)是调节能量代谢的重要组织，其调节作用是通过表达线粒体解偶联蛋白1(UCP1)实现的。支持UCP1和BAT在控制能量平衡中的关键作用的是大量研究结果，这些研究表明UCP1促进了能量消耗。重要的是，最近使用正电子发射断层扫描(PET)的发现表明，BAT活动对人类也很重要，可能受到肥胖、年龄、性别和2型糖尿病的调节。此外，最近的研究表明，白色脂肪组织(WAT)具有显着的可塑性，表达UCP1，并呈现出许多类似于BAT的形态特征。尽管最近有这些重要的观察，但调节蝙蝠活动或Wat的“褐变”的内分泌信号还没有完全被理解，并且对于我们理解控制哺乳动物能量代谢的因素是至关重要的。*5-羟色胺是一种古老的生物胺，存在于整个动物门中，对调节行为、食欲和能量消耗至关重要。人们经常低估的是，人体内绝大多数的5-羟色胺存在于外周，而不是中枢神经系统。色氨酸羟化酶(TPH1)催化从膳食色氨酸合成5-羟色胺的限速步骤。重要的是，缺乏TPH1的小鼠血清5-羟色胺水平降低，但大脑中的5-羟色胺水平正常，从而使我们能够确定外周5-羟色胺在调节外周能量代谢方面的作用。在初步研究中，我们发现循环中的5-羟色胺水平会随着营养状况的变化而改变，包括禁食和高脂肪饮食，并因运动而减少。通过研究缺乏TPH1的小鼠对外周5-羟色胺的遗传操作表明，由于BAT的过度激活和白色脂肪细胞的加速褐化，低水平的5-羟色胺增加了能量消耗。**NSERC Discovery Grant的目的是通过确定5-羟色胺/TPH1在控制脂肪组织能量代谢中的作用，扩展我们在研究能量代谢的激素调节方面的广泛经验。我们将具体研究：**目的1：TPH1的化学抑制是否复制了TPH1基因缺失对身体质量和能量消耗的影响，这种影响是由UCP1介导的吗？*目的2：TPH1和5-羟色胺控制白色和棕色脂肪组织能量代谢的机制是什么？*目的3：TPH1是体力活动/运动引起的白色脂肪褐变所必需的吗？**5-羟色胺是60多年前在寻找引起高血压的血管收缩物质时发现的，它的名字很贴切，因为它存在于血清中(血清)和血管活性特性(托宁)中。对于外周5-羟色胺在控制脂肪组织能量代谢中的新作用，我们现在有了大量的初步数据。这些发现将一种古老的分子与哺乳动物脂肪组织能量代谢的控制联系在一起，这种分子对于调节整个门类的能量平衡至关重要。我们建议的研究将确定5-羟色胺和/或TPH1如何以及为什么控制哺乳动物的能量消耗，以及UCP1是否对这些影响是必不可少的。这项基于发现的研究的影响可能会通过改善营养政策、改善对环境因素的控制以及开发新的疗法对加拿大人产生重要影响，而这只能通过增加对5-羟色胺如何控制脂肪组织代谢和能量平衡的了解来实现。

The goal of our NSERC discovery research program is to understand the regulation of energy metabolism in mammals. Brown adipose tissue (BAT) is an important tissue regulating energy metabolism effects which are mediated through expression of mitochondrial uncoupling protein 1 (UCP1). Supporting a critical role for UCP1 and BAT in the control of energy balance are findings from numerous studies demonstrating that UCP1 promotes energy expenditure. Importantly, recent findings using positron emission tomography (PET) have indicated that BAT activity is also important in humans and may be regulated by obesity, aging, gender and type 2 diabetes. In addition recent studies have demonstrated that there is significant plasticity in white adipose tissue (WAT) to express UCP1 and take on many morphological characteristics analogous to BAT. Despite these recent important observations the endocrine signals regulating BAT activity or the "browning" of WAT are not fully understood and are of fundamental importance to our understanding of factors controlling energy metabolism in mammals. * *Serotonin is an ancient biogenic amine that is found across phyla and is essential for regulating behaviour, appetite and energy expenditure. What is often under-appreciated is that the vast majority of serotonin in the body is found in the periphery, not the central nervous system. Tryptophan hydroxylase (Tph1) catalyzes the rate-limiting step in the synthesis of serotonin from dietary tryptophan. Importantly, mice lacking Tph1 have reduced serum serotonin, but normal levels of serotonin in the brain, thus allowing us to determine the effects of peripheral serotonin in regulating peripheral energy metabolism. In preliminary studies we have found that circulating serotonin levels are altered by nutritional status including fasting and a diet high in fat and are reduced in response to exercise. Genetic manipulation of peripheral serotonin by studying mice deficient in Tph1 have revealed that low levels of serotonin increase energy expenditure as a result of hyper-activation of BAT and increased browning of white adipocytes. **The aims of this NSERC Discovery Grant are to extend on our extensive experience in studying the hormonal regulation of energy metabolism by determining the role of serotonin/Tph1 in controlling adipose tissue energy metabolism. Specifically we will examine: **AIM 1: Does chemical inhibition of Tph1 phenocopy the effects of Tph1 genetic deletion on body mass and energy expenditure and is this effect mediated by UCP1?*AIM 2: What is the mechanism by which Tph1 and serotonin control white and brown adipose tissue energy metabolism? *AIM 3: Is Tph1 required for the browning of white fat induced by physical activity/exercise? **Serotonin was discovered more than 60 years ago while searching for vasoconstrictors that cause hypertension, and was aptly named it for its presence in serum (sero) and its vasoactive properties (tonin). We now have substantial preliminary data for a new role of peripheral serotonin in controlling adipose tissue energy metabolism. These findings link an ancient molecule that is essential for regulating energy balance across phyla to the control of adipose tissue energy metabolism in mammals. Our proposed studies will identify how and why serotonin and/or Tph1 controls energy expenditure in mammals and whether UCP1 is essential for these effects. The impact of this discovery-based research may have an important impact on Canadians through improved nutritional policy, improved control over environmental factors and developing new therapeutics, which can only be achieved through an increased understanding of how serotonin controls adipose tissue metabolism and energy balance.