Ketone Body Metabolism and Integrated Metabolic Homeostasis

描述(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、失代偿糖尿病和坚持低碳水化合物(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：第一，酮在血液中的积累可以促进酮酸中毒--这是由于酮的生成速度和酮体氧化速率不匹配而引起的。其次，根据生理状态的不同，酮提供了高达40%的碳链，这些碳链可以产生高能的磷酸盐。虽然酮症酸中毒的不良后果得到了很好的认识，但到目前为止，实验模型还没有揭示是否可以从能量上容忍酮氧化的丧失。该实验室的初步研究表明，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)的生殖系Oxct1-/-小鼠在出生后第二天后就不能存活。这项拟议的研究将检验一个中心假设，即酮体在选定的生理状态下发挥着专有的能量作用，即酮体氧化缺陷会在新生儿时期和成人营养缺乏期间造成代谢异常。为了具体检验酮分解缺乏的能量效应，独立于酮症酸中毒，该实验室最近还发展了组织特异性Scot功能丧失小鼠模型，该模型将用于以下特定目的。第一个目标将展示新生儿期组织对酮代谢的特定能量需求。使用骨骼肌细胞、心肌细胞和神经元特异的Oxct1-/-小鼠，这些实验有望揭示新生儿时期对酮最依赖的组织(S)。接下来，利用骨骼肌Scot功能丧失的成年小鼠，作为最大的酮类使用者和综合代谢稳态的关键决定因素，第二个目标将确定在摄食状态和长期营养剥夺期间，酮体代谢在全身和骨骼肌代谢中的作用。第三个目标是使用成年心脏功能丧失的小鼠来探索酮的身体代谢在摄食状态和营养缺乏的情况下在这个高能量需求器官中的作用。由于营养剥夺降低了葡萄糖的可获得性，消除酮体氧化预计会引起代谢异常，促进低血糖，当在心肌中消除时，有助于心肌病的发展。综上所述，这些研究将为深入了解酮体代谢在哺乳动物系统中的能量作用提供基本的见解，因此可能最终影响(I)人类新生儿筛查方案，(Ii)成人代谢性疾病新的风险分层生物标记物的开发，以及(Iii)以代谢基因组学为指导的个性化营养方案的开发。

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.