Meal-associated metabolic responses in brown adipose tissue and skeletal muscle related to weight loss

具有代谢活性的棕色脂肪组织（BAT）与心脏代谢疾病的发病率较低有关，并可能有助于预防肥胖。这些有益效果可能是由于葡萄糖和脂质从循环中清除到BAT中的增加、非颤抖性产热和静息能量消耗。较低的冷诱导的BAT活性可能与节俭的代谢型相关，并且这种节俭的个体响应于热量限制显示较少的体重减轻。然而，与啮齿动物相比，人类BAT消耗能量的能力较低。因此，BAT的有益代谢作用不仅是由于产热，而且还由于细胞串扰和器官间通信，后者包括在控制能量摄入中的传入BAT-脑通信。作为一个展示，肠道激素分泌素激活BAT，从而介导内分泌肠道BAT脑轴，促进小鼠和人类的饱足感。膳食诱导的循环中分泌素激增通过棕色脂肪细胞中表达的分泌素受体导致非颤抖性产热的激活，并与BAT中的葡萄糖摄取相关。因此，肠道与BAT通信，BAT充当能量感测器官，将信息中继到大脑以启动进餐终止。本项目将利用不同的非侵入性成像方式（光声断层成像、磁共振成像、红外热成像）对分泌素介导的BAT和SKM代谢进行功能研究。这些成像技术将能够动态监测靶组织中的代谢。这些研究将实现四个目标，旨在（1）分析不同大量营养素对膳食诱导的分泌素激增的影响，（2）比较膳食和寒冷诱导的BAT和SKM激活的个体差异，（3）调查肥胖者肠道-BAT-脑轴的反应性，以及（4）热量限制和/或运动干预对BAT和SKM中膳食诱导的代谢反应的影响。为非侵入性成像技术、代谢和临床研究领域的专家提供了一个独特的合作机会，以便在基线和应对代谢挑战时对瘦对照和肥胖人群的代谢进行深入的表型分析。以这些靶组织对膳食和寒冷诱导的挑战的差异反应为特征的个体代谢型可能作为诊断生物标志物，以开发用于治疗肥胖症患者的个性化干预措施。

Metabolically active brown adipose tissue (BAT) is associated with lower prevalence of cardiometabolic diseases and may contribute to the prevention of obesity. These beneficial effects are likely due to increased clearance of glucose and lipids from the circulation into BAT, non-shivering thermogenesis, and resting energy expenditure. Lower cold-inducible BAT activity may be associated with a thrifty metabotype, and such thrifty individuals show less weight loss in response to caloric restriction. Human BAT, however, has a lower capacity to dissipate energy compared to rodents. The beneficial metabolic effects of BAT are therefore not merely due to thermogenesis, but also due to cellular crosstalk and inter-organ communication, the latter including afferent BAT-brain communication in the control of energy intake. As a showcase, the gut hormone secretin activates BAT, thereby mediating an endocrine gut-BAT-brain-axis that promotes satiation in mice and in humans. The meal-induced surge of secretin in the circulation leads to activation of non-shivering thermogenesis via secretin receptors expressed in brown adipocytes and correlates with glucose uptake in BAT. Thereby, the gut communicates with BAT which acts as an energy sensing organ relaying information to the brain to initiate meal termination. The meal-induced secretin surge is likely to affect multiple organs, as secretin infusion increases glucose uptake not only in BAT, but also in skeletal muscle (SKM).This project will conduct functional studies on BAT and SKM metabolism mediated by secretin using different modalities of non-invasive imaging (optoacoustic tomography, magnetic resonance imaging, infrared thermography). These imaging techniques will enable dynamic monitoring of metabolism in the target tissues. The studies will address four objectives aiming to (1) analyze the impact of different macronutrients on the meal-induced secretin surge, (2) compare individual variation of meal- and cold-induced activation of BAT and SKM, (3) investigate the responsivity of the gut-BAT-brain-axis in people with obesity, and (4) the impact of caloric restriction and/or exercise interventions on meal-induced responses of metabolism in BAT and SKM.The research unit (RU5298) provides a unique opportunity of collaboration for experts in non-invasive imaging technologies, metabolism, and clinical studies to deeply phenotype the metabolism of lean controls and people with obesity at baseline and in response to metabolic challenges. Individual metabotypes characterized by differential responses of these target tissues to meal- and cold-induced challenges could potentially serve as diagnostic biomarkers to develop personalized interventions for the treatment of people with obesity.