Quantitative and functional analysis of brown fat nutrient fluxes in vivo and its role in organ metabolite exchange

体内棕色脂肪营养通量的定量和功能分析及其在器官代谢物交换中的作用

• 批准号: 10316282
• 负责人: David A Guertin
• 金额: $ 55.99万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-04 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316282
• 关键词: Address; Adrenergic beta-Agonists; Adult; Affect; Ammonia; Anabolism; Area; Arginine; Back; Biochemistry; Biology; Blood Circulation; Body Temperature; Brown Fat; Calories; Carbon; Cardiovascular Diseases; Chronic; Citric Acid Cycle; Clinical; Communication; Complex; Consumption; Coupled; Data; Diet; Disease; Energy Metabolism; Engineering; Environment; Enzymes; Epidemic; Fatty acid glycerol esters; Food; Gender; Genetic; Glucose; Glutamates; Glutamine; Goals; Healthcare; High Fat Diet; Homeostasis; Human; Hyperglycemia; Label; Left; Life Style; Lipids; Literature; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Methods; Mitochondria; Modeling; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Overweight; Oxides; Pathology; Pathway interactions; Physiological; Process; Production; Prognosis; Property; Protocols documentation; Reporting; Research; Rest; Role; Sense Organs; Source; Stimulus; Techniques; Technology; Testing; Therapeutic; Thermogenesis; Urea; Venous; Warburg Effect; aerobic glycolysis; angiogenesis; comorbidity; cost; detection of nutrient; diet and exercise; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; improved; in vivo; innovation; lipid metabolism; metabolic fitness; metabolomics; non-alcoholic fatty liver disease; novel; nutrition; oxidation; pandemic disease; response; sedentary lifestyle; stable isotope; synergism; therapeutic target; thermal stress; trend; tumor growth

PROJECT SUMMARY Metabolic syndrome is a pandemic driven by poor nutrition and sedentary lifestyles that is associated with being overweight or obese. Its pathology is complex, and its comorbidities—including type 2 diabetes, cardiovascular disease, NAFLD, and cancer—are devastating. While better diets and exercise can improve prognosis, this alone typically cannot overcome the synergy of genetics, environment, and food engineering that collectively caused this epidemic. The health care and human costs of this pandemic are astronomical, and thus, innovative clinical strategies are needed. What if we could burn off excess calories when at rest, or in combination with lifestyle changes or other therapeutics? Such energy expenditure is the normal function of brown adipose tissue (BAT). Active BAT can convert large quantities of calories into heat (rather than storing them as fat)—a process called non-shivering thermogenesis. BAT is naturally stimulated by cold exposure, by certain high fat diets, and by beta-adrenergic agonists. The presence of BAT in adult humans also protects against metabolic diseases. For this reason, brown fat is often called healthy fat, and studying its biology and therapeutic strategies to stimulate it are now key focus areas of metabolic disease research. Glucose is a major brown fuel and it has been proposed that BAT could function therapeutically as a “glucose sink.” It is often assumed that BAT completely metabolizes glucose to provide energy for thermogenesis despite historical literature arguing that only a small percentage of the glucose BAT consumes is directly oxidized. This raises a fundamental unanswered question in BAT biology—what else is glucose doing? In fact, very little is known about BAT metabolic fluxes in general due to technical limitations in studying in vivo organ metabolism. Here, we combine state-of-the-art technologies in mass spectrometry (MS) coupled with in vivo stable isotope tracing and genetics to overcome previous barriers to understanding the biochemistry of BAT metabolism. In Aim 1, we take advantage of protocols we developed to quantitatively explore how glucose and other metabolites are used by BAT. We also explore how BAT metabolic “fluxes” are affected by environment, diet, and gender. In Aim 2, we explore a specific auxiliary pathway that we discovered through unbiased metabolomics to be upregulated in active BAT. Quantitatively defining the biochemistry of brown fat metabolism and its interplay with other organs is an essential step towards reaching the ultimate goal of harnessing brown fat’s calorie burning power to reverse obesity trends.

项目摘要 代谢综合征是由营养不良和久坐的生活方式驱动的大流行，与 超重或肥胖。它的病理很复杂，合并症 - 包括2型糖尿病， 心血管疾病，NAFLD和癌症是毁灭性的。虽然更好的饮食和运动可以改善 预后，仅此一项通常就无法克服遗传学，环境和食物工程的协同作用 这共同引起了这种流行病。这种大流行的医疗保健和人力成本是天文学的， 因此，需要创新的临床策略。如果我们可以在休息时燃烧多余的卡路里怎么办，或者 结合生活方式的改变或其他治疗剂？这样的能量支出是 棕色脂肪组织（蝙蝠）。活跃的蝙蝠可以将大量卡路里转化为热量（而不是存储 它们是脂肪） - 一种称为非震动的生热作用的过程。蝙蝠自然受到冷暴露的刺激， 某些高脂肪饮食以及β-肾上腺素能激动剂。成人人类的蝙蝠的存在也可以保护 反对代谢疾病。因此，棕色脂肪通常被称为健康脂肪，并研究其生物学和 刺激它的治疗策略现在是代谢疾病研究的关键重点领域。 葡萄糖是主要的棕色燃料 下沉。”通常认为BAT完全代谢葡萄糖以提供热生成的能量 尽管历史文献认为只有一小部分葡萄糖蝙蝠消耗的是直接 氧化。这提出了BAT生物学中的基本未解决的问题 - 葡萄糖还有什么？ 事实，由于体内研究的技术限制，通常对BAT代谢通量知之甚少 器官代谢。在这里，我们在质谱法（MS）中结合了最新技术 体内稳定的同位素追踪和遗传学，以克服以前了解生物化学的障碍 蝙蝠代谢。在AIM 1中，我们利用了我们开发的协议来定量探讨如何 BAT使用葡萄糖和其他代谢产物。我们还探讨了蝙蝠代谢“通量”如何受到 环境，饮食和性别。在AIM 2中，我们探索了我们通过的特定辅助途径 无偏的代谢组学将在主动蝙蝠中进行更新。定量定义棕色脂肪的生物化学 代谢及其与其他器官的相互作用是实现最终目标的重要一步 利用棕色脂肪的卡路里燃烧能力来逆转肥胖趋势。