Hormonal Regulation of Energy Expenditure in Mice

小鼠能量消耗的激素调节

• 批准号: RGPIN-2014-04001
• 负责人: Steinberg, Gregory
• 金额: $ 2.91万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=587544
• 关键词: Hormonal; Regulation; Energy; Expenditure; Mice

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.

我们的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）是一种重要的能量代谢调节组织，其能量代谢调节作用通过线粒体解偶联蛋白1（UCP 1）的表达来介导。支持UCP 1和最佳可得技术在控制能量平衡方面的关键作用的是许多研究的结果，这些研究表明UCP 1促进能量消耗。 重要的是，最近使用正电子发射断层扫描（PET）的研究结果表明，BAT活性在人类中也很重要，可能受到肥胖，衰老，性别和2型糖尿病的调节。 此外，最近的研究表明，在白色脂肪组织（WAT）中存在显著的可塑性，以表达UCP 1并呈现许多类似于BAT的形态学特征。 尽管最近有这些重要的观察结果，但调节BAT活性或WAT的“布朗宁”的内分泌信号尚未完全理解，并且对于我们理解控制哺乳动物能量代谢的因素具有根本重要性。 5-羟色胺是一种古老的生物胺，在整个门中发现，对调节行为，食欲和能量消耗至关重要。 通常被低估的是，体内绝大多数血清素都存在于外周，而不是中枢神经系统。 色氨酸羟化酶（Tph 1）催化从饮食色氨酸合成5-羟色胺的限速步骤。 重要的是，缺乏Tph 1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中的作用。 在初步研究中，我们发现循环中的5-羟色胺水平会因营养状况（包括禁食和高脂肪饮食）而改变，并因运动而降低。通过研究Tph 1缺陷的小鼠对外周血清素进行遗传操作，揭示了低水平的血清素会增加能量消耗，这是BAT过度活化和白色脂肪细胞布朗宁增加的结果。 该NSERC发现资助的目的是通过确定5-羟色胺/Tph 1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丰富经验。 具体来说，我们将研究： 目标1：化学抑制Tph 1表型是否影响Tph 1基因缺失对体重和能量消耗的影响，这种影响是否由UCP 1介导？ 目的2：Tph 1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：Tph 1是身体活动/运动诱导的白色脂肪布朗宁所必需的吗？ 血清素是60多年前在寻找引起高血压的血管收缩剂时发现的，并因其存在于血清中（血清）和其血管活性特性（紧张素）而被恰当地命名。 我们现在有大量的初步数据，外周5-羟色胺在控制脂肪组织能量代谢中的新作用。 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起来，这种分子对于调节整个门的能量平衡至关重要。 我们提出的研究将确定血清素和/或Tph 1如何以及为什么控制哺乳动物的能量消耗，以及UCP 1是否对这些作用至关重要。 这项基于发现的研究的影响可能会对加拿大人产生重要影响，通过改善营养政策，改善对环境因素的控制和开发新的治疗方法，这只能通过增加对血清素如何控制脂肪组织代谢和能量平衡的理解来实现。