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HORMONAL REGULATION OF ENERGY METABOLISM

能量代谢的荷尔蒙调节

基本信息

批准号：
3072496
负责人：
TARUN B. PATEL
金额：
$ 6.52万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-04-01 至 1992-03-31
项目状态：
已结题

项目摘要

Regulation of hepatic gluconeogenesis by hormones such as glucagon, insulin, epinephrine, vasopressin and angiotensin is well established. In contrast, however, relatively few studies have examined the effects of these hormones, on regulation of the various processes involved in energy generation in the liver and heart. It may be expected that stimulation of gluconeogenesis from 3-carbon precursors (eg. pyruvate and lactate) by glucagon or alpha-adrenergic agonist, phenylephrine, would decrease the oxidation of these compounds. However, preliminary data indicate that the alpha-adrenergic agonist, phenylephrine, increases the oxidation of (2-14C) pyruvate both in the perfused rat liver and the perfused working heart preparation, demonstrating that the metabolic flux through the tricarboxylic acid cycle (TCA cycle) is stimulated by alpha-adrenergic stimulation. Therefore, it is the overall objective of this proposal to characterize and elucidate the effect of epinephrine, vasopressin, angiotensin, glucagon and insulin on the key regulatory processes involved in carbohydrate energy metabolism. Initially studies will be performed to elucidate the effects of the various hormones described above on the metabolic flux through the pyruvate dehydrogenase (PDH) complex and the TCA cycle. These and additional studies with (2-14C) labeled acetate will indicate whether the increased TCA cycle activity, during for eg. alpha-adrenergic stimulation of livers and hearts, is a function of increased pyruvate carboxylation or increased metabolic flux through the PDH reaction. Secondly, employing (1-14C) monomethyl alpha-ketoglutarate, as a source of intracellular alpha-ketoglutarate, studies will be performed to investigate the effects of the various hormones on the activity of one of the key regulatory enzymes of the TCA cycle, the alpha-ketoglutarate dehydrogenase complex in intact perfused rat livers and hearts. Employing this approach to overcome cellular impermeability to free alpha-ketoglutarate, this will be the initial attempt, thus far, to elucidate directly the regulation of the alpha-ketoglutarate dehydrogenase complex in an intact perfused organ preparation. Studies in working heart preparations will also investigate the relationship between energy requirements of the tissue (due to alterations in afterload) and activity of the TCA cycle and the alpha-ketoglutarate dehydrogenase complex. This latter approach will also demonstrate if hormone (eg. epinephrine) elicited metabolic alterations are secondary to the inotropic effects of the hormones.

激素对肝脏糖异生的调节高血糖素、胰岛素、肾上腺素、加压素和血管紧张素情况良好已经成立了。然而，相比之下，相对较少的研究研究了这些荷尔蒙对调节肝脏和肝脏中参与能量产生的各种过程心。可以预期，对糖异生的刺激来自3-碳前体(例如丙酮酸和乳酸)由高血糖素或α-肾上腺素能激动剂，苯肾上腺素，会降低氧化这些化合物的氧化。不过，初步数据显示表明α-肾上腺素能激动剂苯肾上腺素，增加灌流液中(2-14C)丙酮酸的氧化大鼠肝脏和灌流的工作心脏制剂，证明了通过三羧酸的代谢通量 α-肾上腺素能刺激酸循环(TCA循环) 刺激。因此，这项建议的总体目标是为了表征和阐明肾上腺素的作用，血管加压素、血管紧张素、胰升糖素和胰岛素的关键参与碳水化合物能量代谢的调节过程。最初将进行研究，以阐明上述各种激素对代谢通量的影响丙酮酸脱氢酶(PDH)复合体和TCA循环。这些研究以及(2-14C)标记醋酸酯的其他研究将指示是否增加的三氯乙酸循环活动，在为例如。 α-肾上腺素能刺激肝脏和心脏，是一种丙酮酸羧化程度增加或代谢通量增加通过PDH反应。其次，使用(1-14C) α-酮戊二酸单甲酯作为胞内物质来源 -酮戊二酸，将进行研究，以调查不同激素对其中一键活性的影响三氯乙酸循环的调节酶--α-酮戊二酸完整灌流大鼠肝脏和心脏中的脱氢酶复合体。使用这种方法来克服细胞的不渗透性自由α-酮戊二酸，这将是第一次尝试，到目前为止，直接阐明α-酮戊二酸的调节完整的灌流器官制剂中的脱氢酶复合体。对工作心脏制剂的研究也将调查组织能量需求之间的关系(由于后负荷的变化)和TCA循环的活动性 α-酮戊二酸脱氢酶复合体。后一种方法还将展示荷尔蒙(例如，肾上腺素)引起的代谢改变是次要的肌力作用。荷尔蒙。