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）：酮体是一种狂热的细胞燃料来源，在新生儿时期，饥饿，糖尿病的糖尿病，饥饿，糖尿病的含量和粘附在低碳水化合物（例如，阿特金斯）饮食中产生。已知酮在代谢上很重要，原因有两个：首先，它们的血液积累可以促进酮症酸中毒 - 酮症发生率与酮体体氧化速率之间的不匹配引起。其次，根据生理状态，酮供应高达高能磷酸盐的碳骨架的40％。尽管酮症酸中毒的不利后果是充分欣赏的，但迄今为止，实验模型尚未揭示酮氧化的丧失是否可以在能量上耐受性耐受性。该实验室的初步研究表明，缺乏对酮体利用至关重要的酶的生殖线OXCT1 - / - 小鼠，琥珀酸-COA：3-氧化转移酶（SCOT），在第二天后第二天后是不可行的。拟议的研究将检验一个中心假设，即酮体在某些生理状态中发挥了强大的能量作用，因为酮体氧化的缺陷在新生儿时期和成人成人的养分剥夺期间会产生代谢异常。为了特别检查酮酸缺乏症的能量影响，与酮症酸中毒无关，该实验室最近还开发了组织特异性的SCOT功能丧失小鼠模型，这些模型将在以下特定目的中使用。第一个目的将证明在新生儿时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，这些实验有望在新生儿期间揭示最依赖酮的组织。接下来，使用成年小鼠在骨骼肌中失效的功能丧失，总体是最大的酮使用者，并且是综合代谢稳态的关键决定因素，第二个目标将决定酮体内代谢在全身和骨骼肌代谢中的作用，而在美联储状态和在繁殖的营养剥夺过程中。第三个目标将使用成年小鼠心脏损失的成年小鼠来探索酮体代谢在这种高能量征用器官中在美联储状态和营养剥夺的情况下的作用。由于营养剥夺会降低葡萄糖的可用性，因此消除酮体氧化有望引起代谢异常，促进低血糖，并且在心脏肌肉中消除时，会导致心肌病的发展。综上所述，这些研究将提供对酮体代谢在哺乳动物系统中的能量作用的基本见解，因此最终可能会影响（i）人类新生儿筛查方案，目前未测试酮酮代谢的离散性疾病，（ii）对成年生物疾病的开发以及（II）对成人疾病的开发（II II II III）的发展（II II II III）的发展（II）方案。