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: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=566231
• 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.

我们国家科学研究委员会发现研究计划的目标是了解哺乳动物能量代谢的调节。褐色脂肪组织（Brown aditissue， BAT）是调节能量代谢的重要组织，其作用是通过表达线粒体解偶联蛋白1 （mitochondrial uncoupling protein 1, UCP1）介导的。大量研究表明，UCP1促进能量消耗，UCP1和BAT在控制能量平衡中起着关键作用。重要的是，最近使用正电子发射断层扫描（PET）的发现表明，BAT活性在人类中也很重要，可能受肥胖、衰老、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）表达UCP1具有显著的可塑性，并具有许多类似于BAT的形态特征。尽管最近有这些重要的观察结果，但调节BAT活性或WAT“褐变”的内分泌信号尚未完全被理解，这对我们理解哺乳动物控制能量代谢的因素至关重要。5 -羟色胺是一种古老的生物胺，存在于各个门中，对调节行为、食欲和能量消耗至关重要。经常被低估的是，体内绝大多数血清素存在于外围神经系统，而不是中枢神经系统。色氨酸羟化酶（Tph1）在膳食色氨酸合成血清素的限速步骤中起催化作用。重要的是，缺乏Tph1的小鼠血清血清素减少，但大脑中血清素水平正常，从而使我们能够确定外周血清素在调节外周能量代谢中的作用。在初步研究中，我们发现循环血清素水平会因营养状况（包括禁食和高脂肪饮食）而改变，并因运动而降低。通过研究Tph1缺陷小鼠对外周血5 -羟色胺的遗传操作表明，低水平的5 -羟色胺会增加能量消耗，这是由于BAT过度激活和白色脂肪细胞褐变增加的结果。这项NSERC发现基金的目的是通过确定血清素/Tph1在控制脂肪组织能量代谢中的作用，扩展我们在能量代谢激素调节研究方面的丰富经验。具体来说，我们将研究：AIM 1：化学抑制Tph1表型是否会影响Tph1基因缺失对体重和能量消耗的影响，这种影响是否由UCP1介导？目的2:Tph1和血清素控制白色和棕色脂肪组织能量代谢的机制是什么？AIM 3：体育活动/运动引起的白色脂肪褐变是否需要Tph1 ？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（sero）和血管活性（tonin）而被恰当地命名为血清素。我们现在有大量的初步数据表明外周血清素在控制脂肪组织能量代谢中的新作用。这些发现将一种对调节跨门能量平衡至关重要的古老分子与哺乳动物脂肪组织能量代谢的控制联系起来。我们提出的研究将确定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是否对这些作用至关重要。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和开发新的治疗方法对加拿大人产生重要影响，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。