Metabolic Regulation of PEPCK Isozymes

人体葡萄糖和脂质代谢的相互作用对维持正常能量平衡至关重要。长期以来，人们都知道糖尿病与脂质代谢障碍有关，脂质代谢障碍以一种不明确的方式导致了疾病的并发症。J. Denis McGary在一篇名为《如果闵可夫斯基有音乐天赋会怎样？》《关于糖尿病的另一种角度》（a Alternative Angle on Diabetes, 1）认为传统的糖尿病研究侧重点错误，从脂质代谢异常的角度来理解胰岛素抵抗和高血糖可能是最好的。脂肪组织脂肪酸再酯化率的降低可能是调节脂肪酸向肝脏输送的关键因素。1968年，我们首次描述了脂肪组织中脂肪酸再酯化的途径，称为甘油生成，随后被证明是脂肪组织和肝脏中甘油三酯合成所需的3-甘油磷酸生成的重要因素。该途径可能在控制脂肪组织和肝脏中甘油三酯的合成以及控制饥饿时脂肪组织中脂肪酸的通量中发挥重要作用。在这一途径中，大鼠控制步骤PEPCK基因的组织特异性表达在小鼠中被抑制，导致脂肪肝的发展和缺乏正常生长。本资助申请所述的研究将探索哺乳动物组织中甘油生成的生理意义，并通过控制游离脂肪酸向肝脏的输送速率来确定PEPCK在糖尿病调节中的作用。此外，PEPCK在肾脏、小肠、大脑、骨骼肌和棕色脂肪组织等组织中的作用将通过转基因小鼠来确定。

The interaction of glucose and lipid metabolism in humans is critical for maintaining normal energy balance. Diabetes has long been known to involve impairment in lipid metabolism that contributes in an ill-defined manner to the complications of the disease. J. Denis McGary, in a provocative article entitled What if Minkowski had been Ageusic? An Alternative Angle on Diabetes, (1) suggested traditional research on diabetes had the wrong emphasis and that insulin resistance and hyperglycemia might best be understood if viewed from the context of an abnormality on lipid metabolism. A decreased rate of fatty acid re-esterfication by adipose tissue could be a critical factor in regulating the delivery of fatty acids to the liver. In 1968, we first described a pathway for the re- esterfication of fatty acids in adipose tissue, termed glyceroneogenesis, that has subsequently been shown to be a significant factor in the generation of 3-glycerolphosphate required for triglyceride synthesis in both adipose tissue and liver. This pathway may play an important role in the control of triglyceride synthesis in adipose tissue and liver and control the flux of fatty acids from adipose tissue during starvation. The tissue-specific expression of the gene for the rat controlling step in this pathway, PEPCK, has been ablated in mice causing the development of fatty liver and a lack of normal growth. The research described in this grant application will explore the physiological significance of glyceroneogenesis in mammalian tissues and establish the role of PEPCK in the regulation of diabetes by controlling the rate of free fatty acid delivery to the liver. In addition, the role of PEPCK in tissue such as kidney, small intestine, brain, skeletal muscle and brown adipose tissue will be determined using genetically modified mice.