Impact of exercise and nutritional manipulations on inflammatory function in humans

我的NSERC研究的长期目标是了解人类新陈代谢和炎症之间的相互作用。使用综合生理学方法，其中运动和营养用于改变代谢并研究对免疫细胞的影响，我们推进了对代谢和炎症领域的理解。未来五年，我们有两个短期目标。* 1)确定运动强度和模式如何影响抗炎细胞因子功能，以及相关机制。2)确定营养性酮症如何影响免疫细胞表型和功能。**我们最近的研究结果表明，运动降低了IL 10和IL 6的抗炎作用，并且高强度间歇训练（HIIT）比中等强度连续训练（MICT）的影响更大。然而，我们的研究仅限于短期训练前后的空腹血液样本，设计无法区分运动强度与模式的影响。因此，我们将使用在急性（单次）运动或慢性运动训练（12周）后特定时间点获得的血液样本进行时间过程实验。参与者将完成HIIT、高强度持续训练（HICT）或与运动持续时间和运动量相匹配的MICT，以隔离运动强度或模式的影响。主要结果是IL 10/IL 6功能，通过测量这些抗炎细胞因子抑制运动前后获得的全血培养物中TNF-α分泌的能力来评估。将测量由IL 10和IL 6激活的细胞内信号传导途径以提供机制见解。以前的研究已经测量了运动后循环中的IL 10和IL 6，并推断出抗炎作用。我们的工作是第一次探索这些细胞因子如何发挥作用，因此将为运动如何影响免疫细胞表型和功能提供新的理解。为了解决第二个目标，我们将使用新开发的外源性酮补充剂，提高循环β-羟基丁酸（BHB）浓度，而不需要限制性饮食的混杂影响。我们将研究酮补充剂在一天和四周内的急性影响，以研究提高BHB如何影响代谢和炎症。主要免疫结局将是在酮补充前后获得的全血培养物中评估的半胱天冬酶-1活化和细胞因子分泌。这些研究将有助于确定营养性酮症是否对白细胞有直接影响，并扩大我们对B-OHB如何作为信号分子整合代谢状态和免疫功能的理解。影响：这个NSERC研究计划将以综合的方式操纵代谢并研究原代人类免疫细胞中的分子通路。这些发现将在免疫代谢领域提供重要的新信息，与人类生理学直接相关。

The long-term objective of my NSERC research is to understand the interactions between metabolism and inflammation in humans. Using an integrative physiology approach where exercise and nutrition are used to alter metabolism and study the effects on immune cells, we advance understanding in the fields of metabolism and inflammation. We have two short-term objectives for the next 5 years.******1) To determine how exercise intensity and pattern impact anti-inflammatory cytokine function, and the mechanisms involved.******2) To determine how nutritional ketosis impacts immune cell phenotype and function.******Our recent findings indicate that exercise reduces the anti-inflammatory action of IL10 and IL6, and that there was a greater impact of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT). However, our study was limited to fasting blood samples before and after short-term training and the design could not separate the influence of exercise intensity vs. pattern. Accordingly, we will perform time course experiments with blood samples obtained at specific timepoints after acute (single bout) exercise or chronic exercise training (12 wk). Participants will complete HIIT, high-intensity continuous training (HICT), or MICT matched for exercise duration and volume to isolate the impact of exercise intensity or pattern. The main outcomes are IL10/IL6 function, assessed by measuring the ability of these anti-inflammatory cytokines to inhibit TNF-alpha secretion in whole blood cultures from samples obtained before and after exercise. Intracellular signalling pathways activated by IL10 and IL6 will be measured to provide mechanistic insight. Previous research has measured circulating IL10 and IL6 following exercise and inferred anti-inflammatory effects. Our work is the first to explore how these cytokines function and will therefore provide new understanding of how exercise impacts immune cell phenotype and function.******To address the second objective, we will use newly developed exogenous ketone supplements that raise circulating beta-hydroxybutyrate (BHB) concentration without the need and confounding influence of restrictive diets. We will study the acute impacts of ketone supplementation on a single day and over four weeks to examine how raising BHB impacts metabolism and inflammation. The major immune outcomes will be caspase-1 activation and cytokine secretion assessed in whole blood cultures obtained before and after ketone supplementation. These studies will help determine whether nutritional ketosis has direct effects on leukocytes and expand our understanding of how B-OHB acts as a signaling molecule to integrate metabolic state and immune function.******Impact: This NSERC research program will manipulate metabolism and study molecular pathways in primary human immune cells in an integrated fashion. Findings will provide important new information in the field of immunometabolism with direct relevance to human physiology.**