Ketone Body Metabolism and Integrated Metabolic Homeostasis

酮体代谢和综合代谢稳态

• 批准号: 8928371
• 负责人: Peter A Crawford
• 金额: $ 35.1万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-06 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928371
• 关键词: Adherence; Adult; Atkins Diet; Biological Markers; Birth; Blood; Body Weight decreased; Brain; Carbohydrates; Carbon; Cardiac Myocytes; Cardiomyopathies; Citric Acid Cycle; Development; Diabetes Mellitus; Disease; Disease Management; Engineering; Enzymes; Epilepsy; Exhibits; Experimental Models; Fatty Acids; Glucose; Heart; Hepatic; Homeostasis; Hour; Human; Hypoglycemia; Impairment; Individual; Infant; Ketone Bodies; Ketones; Label; Laboratories; Laboratory Study; Liver; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Mus; Muscle Fibers; Mutant Strains Mice; Myocardial; Myocardium; Neonatal; Neonatal Screening; Neurons; Nutrient; Nutritional; Organ; Physiological; Prevention; Regimen; Relative (related person); Risk; Role; Skeletal Muscle; Source; Starvation; Sudden infant death syndrome; System; Testing; Tissues; Transferase; Transgenic Organisms; Vertebral column; adverse outcome; clinical care; deprivation; fatty acid oxidation; feeding; flexibility; glucose metabolism; glucose transport; heart metabolism; in vivo; inorganic phosphate; insight; ketogenesis; mouse model; muscle metabolism; novel; oxidation; postnatal; prospective; recombinase; research study; response; succinyl-coenzyme A

DESCRIPTION (provided by applicant): Ketone bodies are an avidly oxidized cellular fuel source, produced in abundance during the neonatal period, starvation, decompensated diabetes, and by adherence to low-carbohydrate (e.g., Atkins) diets. Ketones are known to be metabolically important for two reasons: first, their accumulation in blood can promote ketoacidosis - elicited by mismatch between rates of ketogenesis and ketone body oxidation. Second, depending on physiological state, ketones supply up to 40% of the carbon backbones that yield high-energy phosphates. While the adverse consequences of ketoacidosis are well-appreciated, experimental models to date have not revealed whether loss of ketone oxidation can be energetically tolerated. Preliminary studies from this laboratory show that germline Oxct1-/- mice, which lack the enzyme critical for ketone body utilization, succinyl-CoA:3-oxo-transferase (SCOT), are not viable after the second postnatal day. The proposed study will test the central hypothesis that ketone bodies serve an obligate energetic role in select physiological states, in that deficiencies of ketone body oxidation create metabolic abnormalities in the neonatal period and during nutrient deprivation in the adult. To specifically examine the energetic effects of ketolytic deficiency, independent of ketoacidosis, this laboratory also recently developed tissue-specific loss-of-SCOT-function mouse models that will be used within the following Specific Aims. The first aim will demonstrate the tissue- specific energetic requirement for ketone metabolism in the neonatal period. Using skeletal myocyte-, cardiac myocyte-, and neuron-specific Oxct1-/- mice, these experiments are expected to reveal the tissue(s) most dependent on ketones during the neonatal period. Next, using adult mice with loss-of-SCOT-function in skeletal muscle, collectively the largest ketone user and a key determinant of integrated metabolic homeostasis, the second aim will determine the role of ketone body metabolism in whole-body and skeletal muscle metabolism in the fed state and during prolonged nutrient deprivation. The third aim will use adult mice with loss-of-SCOT-function in heart to explore the role of ketone body metabolism in this high energy-requiring organ in the fed state and in the setting of nutrient deprivation. Because nutrient deprivation decreases glucose availability, elimination of ketone body oxidation is expected to elicit metabolic abnormalities, promote hypoglycemia, and when eliminated in cardiac muscle, contribute to the development of cardiomyopathy. Taken together, these studies will provide fundamental insight into the energetic roles of ketone body metabolism in a mammalian system, and therefore could ultimately influence (i) human newborn screening regimens, which currently do not test discrete disorders of ketone metabolism, (ii) the development of new risk- stratifying biomarkers for adult metabolic disease, and (iii) the development of individualized metabogenomics- guided nutritional regimens.

描述（由申请人提供）：酮体是一种强烈氧化的细胞燃料来源，在新生儿期、饥饿、失代偿性糖尿病以及坚持低碳水化合物（例如阿特金斯）饮食期间大量产生。众所周知，酮在代谢上很重要，原因有两个：首先，它们在血液中的积累会促进酮症酸中毒——这是由生酮速率和酮体氧化速率不匹配引起的。其次，根据生理状态，酮可提供高达 40% 的碳主链，从而产生高能磷酸盐。虽然酮症酸中毒的不良后果已广为人知，但迄今为止的实验模型尚未揭示是否可以积极耐受酮氧化的丧失。该实验室的初步研究表明，种系 Oxct1-/- 小鼠缺乏对酮体利用至关重要的酶琥珀酰辅酶 A:3-氧代转移酶 (SCOT)，在出生后第二天就无法存活。拟议的研究将检验一个中心假设，即酮体在特定的生理状态下发挥着强制性的能量作用，因为酮体氧化的缺陷会导致新生儿期和成人营养缺乏期间的代谢异常。为了专门检查酮解缺乏症的能量影响（独立于酮症酸中毒），该实验室最近还开发了组织特异性 SCOT 功能丧失小鼠模型，该模型将用于以下具体目标。第一个目标将证明新生儿期酮代谢的组织特异性能量需求。使用骨骼肌细胞、心肌细胞和神经元特异性 Oxct1-/- 小鼠，这些实验有望揭示新生儿期最依赖酮的组织。接下来，使用骨骼肌中 SCOT 功能丧失的成年小鼠，它们是最大的酮使用者，也是综合代谢稳态的关键决定因素，第二个目标将确定在进食状态和长期营养缺乏期间酮体代谢在全身和骨骼肌代谢中的作用。第三个目标将使用心脏 SCOT 功能丧失的成年小鼠来探索在进食状态和营养缺乏的情况下酮体代谢在这个高能量需求器官中的作用。由于营养缺乏会降低葡萄糖的利用率，因此酮体氧化的消除预计会引起代谢异常，促进低血糖，并且当在心肌中消除时，会导致心肌病的发展。总而言之，这些研究将为哺乳动物系统中酮体代谢的能量作用提供基本见解，因此可能最终影响（i）人类新生儿筛查方案，该方案目前不测试酮代谢的离散疾病，（ii）成人代谢疾病新的风险分层生物标志物的开发，以及（iii）个体化代谢基因组学指导营养的开发 治疗方案。