Ketone Body Metabolism and Integrated Metabolic Homeostasis

描述（由申请人提供）：酮体是一种易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）饮食时大量产生。酮在代谢方面的重要作用有两个原因：首先，它们在血液中的积累会促进酮症酸中毒——由酮生成速率和酮体氧化速率不匹配引起。其次，根据生理状态，酮类提供高达40%的碳骨架，产生高能磷酸盐。虽然酮症酸中毒的不良后果得到了很好的认识，但迄今为止的实验模型尚未揭示酮氧化损失是否可以在能量上耐受。该实验室的初步研究表明，生殖系Oxct1-/-小鼠缺乏对酮体利用至关重要的酶，琥珀酰辅酶a:3-氧转移酶（SCOT），在出生后第二天就不能存活。拟议的研究将检验酮体在选择的生理状态中起必需的能量作用的中心假设，因为酮体氧化缺陷会在新生儿期和成人营养剥夺期间产生代谢异常。为了专门研究独立于酮症酸中毒的酮解缺乏对能量的影响，该实验室最近还开发了组织特异性scot功能丧失小鼠模型，该模型将用于以下特定目的。第一个目的是证明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，这些实验有望揭示在新生儿时期最依赖酮类的组织。接下来，使用骨骼肌scot功能丧失的成年小鼠（骨骼肌是最大的酮使用者，也是综合代谢稳态的关键决定因素），第二个目标将确定酮体代谢在喂食状态和长期营养剥夺下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，探索在喂食状态和营养剥夺的情况下，酮体代谢在这个高能量需要器官中的作用。由于营养剥夺降低了葡萄糖的可用性，酮体氧化的消除有望引起代谢异常，促进低血糖，并且当在心肌中消除时，有助于心肌病的发展。综上所述，这些研究将对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，目前尚不能检测酮代谢的离散紊乱，（ii）成人代谢性疾病的新风险分层生物标志物的发展，以及（iii）个性化代谢基因组学指导的营养方案的发展。

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.