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

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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.