Ketone Body Metabolism and Integrated Metabolic Homeostasis

描述（由申请人提供）：酮体是一种强烈氧化的细胞燃料源，在新生儿期、饥饿、失代偿性糖尿病期间大量产生，并通过坚持低碳水化合物（例如，阿特金斯）饮食。已知酮在代谢上很重要，原因有两个：首先，其在血液中的蓄积可促进酮症酸中毒-由生酮和酮体氧化速率之间的不匹配引起。其次，根据生理状态，酮提供高达40%的碳骨架，产生高能磷酸盐。虽然酮症酸中毒的不良后果是众所周知的，但迄今为止的实验模型尚未揭示酮氧化的损失是否可以在能量上耐受。该实验室的初步研究表明，缺乏酮体利用关键酶琥珀酰辅酶A：3-氧代转移酶（SCOT）的种系Oxct 1-/-小鼠在出生后第二天后无法存活。拟定研究将检验中心假设，即酮体在选定生理状态中发挥专性能量作用，因为酮体氧化不足会导致新生儿期和成人营养缺乏期间的代谢异常。为了专门研究与酮症酸中毒无关的溶酮缺乏症的能量效应，该实验室最近还开发了组织特异性SCOT功能丧失小鼠模型，将用于以下特定目的。第一个目标是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Oxct 1-/-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（总体上是最大的酮使用者和综合代谢稳态的关键决定因素），第二个目的将确定酮体代谢在进食状态和长期营养剥夺期间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，探索酮体代谢在进食状态和营养剥夺环境中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，因此预计酮体氧化的消除会引起代谢异常，促进低血糖，并且当在心肌中消除时，会导致心肌病的发生。总之，这些研究将提供对哺乳动物系统中酮体代谢的能量作用的基本见解，因此可能最终影响（i）人类新生儿筛查方案，其目前不测试离散的酮代谢疾病，（ii）成人代谢疾病的新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的营养方案的开发。

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.