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

代谢活跃的棕色脂肪组织（BAT）与较低的心脏代谢疾病患病率相关，并可能有助于预防肥胖。这些有益的影响可能是由于葡萄糖和脂质从循环中进入BAT，非寒颤产热和静息能量消耗的清除增加。较低的冷诱导型BAT活性可能与节俭的代谢型有关，而这种节俭的个体在热量限制下表现出较少的体重减轻。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仅是由于产热作用，还由于细胞串扰和器官间通讯，后者包括传入BAT-脑通讯，以控制能量摄入。作为展示，肠道激素分泌素激活BAT，从而介导肠道-BAT-脑内分泌轴，促进小鼠和人类的饱腹感。饮食诱导的分泌素在循环中激增，通过褐色脂肪细胞中表达的分泌素受体激活非寒颤产热，并与BAT中的葡萄糖摄取相关。因此，肠道与BAT沟通，BAT作为能量感知器官，将信息传递给大脑，以启动用餐终止。饮食诱导的分泌素激增可能会影响多个器官，因为分泌素输注不仅会增加BAT的葡萄糖摄取，还会增加骨骼肌（SKM）的葡萄糖摄取。本项目将采用不同的无创成像方式（光声成像、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。这些成像技术将使动态监测代谢的目标组织。这些研究将针对以下四个目标：(1)分析不同常量营养素对饮食诱导的分泌素激增的影响；(2)比较饮食和寒冷诱导的BAT和SKM激活的个体差异；(3)研究肥胖人群肠道-BAT-脑轴的反应性；(4)热量限制和/或运动干预对饮食诱导的BAT和SKM代谢反应的影响。该研究单元（RU5298）为非侵入性成像技术、代谢和临床研究方面的专家提供了一个独特的合作机会，以深入研究瘦对照者和肥胖人群的代谢表型，并应对代谢挑战。以这些靶组织对食物和寒冷诱导的挑战的不同反应为特征的个体代谢型可能作为诊断性生物标志物，为肥胖患者的治疗开发个性化干预措施。

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.