Temperature Sensing and the Regulation of Fuel Metabolism

我的NSERC项目的长期目标是研究环境、营养和运动压力因素如何调节脂肪组织和肝脏代谢，其中的潜在机制，以及这如何影响全身碳水化合物和脂肪的稳态。为了解决这些基本问题，我们使用啮齿动物模型结合细胞/组织培养方法，并检查从全身能量消耗到基因表达调节的端点。在过去的6年里，我们发表了58篇论文，其中22篇是由我作为高级/通讯作者，由HQP主持的NSERC资助的，其中许多论文获得了NSERC奖学金（3篇PGS-D， 3篇CGS-D， 2篇CGS-M）。我们已经证明，在其他发现中，定期进行运动可以保护免受免疫代谢挑战，运动诱导的信号因子白细胞介素6 （IL-6）增强肝脏胰岛素作用，IL-6信号在慢性营养过剩的情况下通过内质网应激机制减弱。我们已经开始探索的一个新方向是冷应激对脂肪组织和全身代谢的影响。我们已经从几个不同的角度研究了这个广泛的问题，从这个新的研究领域得到的发现，作为当前应用的基础，证明了胰高血糖素参与了寒冷诱导白色脂肪组织适应的机制，住房温度对脂肪组织对运动的反应有深远的影响。而间歇性的寒冷暴露会使葡萄糖稳态受损导致的贪食和体重增加脱钩。在这些发现的基础上，并进一步以令人兴奋的初步数据为指导，在接下来的5年里，我们将研究寒冷的感觉是如何触发代谢适应的，特别是研究冷感知阳离子通道TRPM8（瞬时受体电位阳离子通道亚家族美拉他汀成员8）在这些过程中的作用。在前两个目标中，我们将解读TRPM8激活急性增加产热的机制（目的1）以及TRPM8的重复激活如何诱导线粒体/产热基因和蛋白质的表达（目的2）。在Aim 3中，我们将研究TRPM8在介导对寒冷的代谢反应中的必要性，在Aim 4中，我们将探索TRPM8激活与运动在调节脂肪组织和全身代谢中的相互作用。本提案中概述的实验将增加我们对脂肪组织生物学以及这些变化如何影响全身燃料代谢的基本，基本的理解。一个多样化的HQP群体将获得丰富的培训经验，这将为他们在自然科学领域的职业生涯或进一步培训做好准备。

The long-term objective of my NSERC program is to examine how environmental, nutritional and exercise stressors modulate adipose tissue and liver metabolism, the underlying mechanisms therein, and how this influences systemic carbohydrate and fat homeostasis. To address these basic, fundamental questions, we use rodent models coupled with cell/tissue culture approaches and examine endpoints ranging from whole body energy expenditure to the regulation of gene expression. Over the past 6 years we have published 58 papers, 22 that were NSERC funded with myself as senior/corresponding author and led by HQP, many of whom were supported by NSERC scholarships (3 PGS-D, 3 CGS-D, 2 CGS-M). We have demonstrated, amongst other findings, that regularly performed exercise confers protection against immuno-metabolic challenges, that the exercise inducible signaling factor interleukin 6 (IL-6) enhances liver insulin action, and that IL-6 signaling is attenuated in conditions of chronic nutrient excess, through a mechanism involving endoplasmic reticulum stress. A new direction we have started to explore is the impact of cold stress on adipose tissue and systemic metabolism. We have examined this broad question from several different perspectives and findings from this new line of research, which serve as the basis for the current application, demonstrated that glucagon is involved in the mechanisms through which cold induces adaptations in white adipose tissue, that housing temperature has profound effects on the response of adipose tissue to exercise, and that intermittent cold exposure uncouples hyperphagia and weight gain from impairments in glucose homeostasis. Building upon these discoveries, and further guided by exciting preliminary data, over the next 5 years we will examine how the sensation of cold triggers metabolic adaptations, specifically examining the role of the cold sensing cation channel TRPM8 (Transient Receptor Potential cation channel subfamily Melastatin member 8) in these processes. In the first two aims we will decipher the mechanisms through which activation of TRPM8 acutely increases thermogenesis (Aim 1) and how the repeated activation of TRPM8 induces the expression of mitochondrial/thermogenic genes and proteins (Aim 2). In Aim 3 we will investigate the necessity of TRPM8 in mediating the metabolic response to cold and in Aim 4 will explore interactions between TRPM8 activation and exercise in the regulation of adipose tissue and systemic metabolism. The experiments outlined in this proposal will increase our basic, fundamental understanding of adipose tissue biology and how these changes impact systemic fuel metabolism. A diverse group of HQP will receive a rich training experience which will prepare them for careers, or further training, in the natural sciences.