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 代谢综合征是一种由营养不良和久坐不动的生活方式引起的流行病， 超重或肥胖。它的病理是复杂的，它的合并症-包括2型糖尿病， 心血管疾病、非酒精性脂肪肝和癌症-是毁灭性的。虽然更好的饮食和锻炼可以改善 预后，这本身通常不能克服遗传，环境和食品工程的协同作用， 共同导致了这场流行病。这一流行病的医疗保健和人力成本是天文数字， 因此，需要创新的临床策略。如果我们可以在休息时燃烧掉多余的卡路里， 结合生活方式的改变或其他疗法这种能量消耗是正常的功能， 棕色脂肪组织（BAT）。活性BAT可以将大量的卡路里转化为热量（而不是储存）。 它们作为脂肪）--一个称为非颤抖产热的过程。BAT自然受到冷暴露的刺激， 某些高脂肪饮食和β-肾上腺素能激动剂。BAT在成年人中的存在也可以保护 对抗代谢性疾病因此，棕色脂肪通常被称为健康脂肪，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焦点领域。 葡萄糖是一种主要的棕色燃料，并且已经提出BAT可以作为“葡萄糖”在治疗上起作用。 下沉”通常假设BAT完全代谢葡萄糖以提供产热能量 尽管历史文献认为BAT消耗的葡萄糖中只有一小部分直接 被氧化了这就引出了BAT生物学中一个尚未回答的基本问题--葡萄糖还有什么作用？在 事实上，由于体内研究的技术限制，一般对BAT代谢通量知之甚少 器官代谢在这里，我们将联合收割机最先进的质谱技术与 体内稳定同位素示踪和遗传学，以克服以前的障碍，了解生物化学 BAT代谢。在目标1中，我们利用我们开发的协议来定量探索如何 葡萄糖和其他代谢物被最佳可得技术利用。我们还探讨了BAT代谢“通量”如何受到 环境、饮食和性别。在目标2中，我们探索了一种特定的辅助途径， 无偏见的代谢组学将在活跃的BAT中上调。定量定义棕色脂肪的生物化学 新陈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， 利用棕色脂肪燃烧卡路里的能力来扭转肥胖趋势。