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)与心脏代谢性疾病的发病率较低有关，可能有助于预防肥胖。这些有益的影响可能是由于增加了葡萄糖和脂肪从循环进入BAT的清除，不颤抖的生热作用，以及静息能量消耗。较低的冷诱导蝙蝠活动可能与节俭的代谢型有关，这种节俭的人对卡路里限制的反应显示出较少的体重减轻。然而，与啮齿动物相比，人类蝙蝠的能量消耗能力较低。因此，蝙蝠有益的新陈代谢效应不仅是由于产热作用，还因为细胞串扰和器官间通讯，后者包括控制能量摄入的传入蝙蝠-大脑通讯。作为展示，胃肠激素分泌素激活蝙蝠，从而调节内分泌肠道-蝙蝠-脑轴，促进小鼠和人类的饱腹感。膳食诱导循环中的分泌素激增，通过棕色脂肪细胞表达的分泌素受体激活非颤抖的产热作用，并与蝙蝠的葡萄糖摄取相关。因此，肠道与蝙蝠进行交流，蝙蝠充当能量感应器，将信息传递给大脑，以启动进食终止。膳食诱导的分泌素激增可能影响多个器官，因为分泌素的输注不仅增加了蝙蝠体内的葡萄糖摄取，而且还增加了骨骼肌(SKM)的葡萄糖摄取。本项目将使用不同的非侵入性成像(光声断层扫描、磁共振成像、红外热像)对促胰液素介导的BAT和SKM代谢进行功能研究。这些成像技术将能够动态监测目标组织的新陈代谢。这些研究将着眼于四个目标：(1)分析不同的常量营养素对膳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)调查肥胖者肠道-蝙蝠-脑轴的响应性；(4)热量限制和/或运动干预对BAT和SKM的膳食诱导的代谢反应的影响。研究单位(RU5298)为非侵入性成像技术、代谢、以及临床研究，以深入研究瘦身对照组和肥胖者在基线和应对代谢挑战时的代谢情况。以这些靶组织对饮食和寒冷诱导的挑战的不同反应为特征的个体代谢型可能成为诊断生物标记物，为肥胖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.