HORMONAL REGULATION OF ENERGY METABOLISM

通过激素如 胰高血糖素、胰岛素、肾上腺素、血管加压素和血管紧张素 确立了习 然而，相比之下， 研究了这些激素对调节 肝脏中能量产生的各种过程， 心 可以预期，刺激胚胎发育 从3-碳前体（例如，丙酮酸和乳酸） 或α-肾上腺素能激动剂，苯肾上腺素，会减少 氧化这些化合物。 然而，初步数据 表明α-肾上腺素能激动剂苯肾上腺素 增加（2- 14 C）丙酮酸的氧化， 大鼠肝脏和灌流工作心脏制剂， 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，本建议的总体目标是 为了表征和阐明肾上腺素的作用， 加压素、血管紧张素、胰高血糖素和胰岛素对关键 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）复合物和TCA循环。 这些和其他使用（2- 14 C）标记醋酸盐的研究将 表明是否增加TCA循环活动，例如。 肝脏和心脏的α-肾上腺素能刺激，是一种功能， 丙酮酸羧化增加或代谢通量增加 通过PDH反应。 其次，采用（1- 14 C） α-酮戊二酸单甲酯，作为细胞内 α-酮戊二酸，将进行研究以调查 各种激素对其中一种关键的 TCA循环的调节酶，α-酮戊二酸 脱氢酶复合物的完整灌注大鼠肝脏和心脏。 采用这种方法来克服细胞的不渗透性， 游离的α-酮戊二酸，这将是迄今为止， 直接阐明α-酮戊二酸的调节 脱氢酶复合物在完整的灌注器官制备。 工作心脏准备的研究也将调查 组织的能量需求之间的关系（由于 后负荷的改变）和TCA循环的活性， α-酮戊二酸脱氢酶复合物。 后一种方法 也将证明如果激素（例如，肾上腺素） 代谢改变继发于 荷尔蒙

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.