The objective of these studies was to determine the molecular basis for the activation of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription during prolonged submaximal exercise. Mice were fed a high-carbohydrate diet for 1 wk and exercised continuously by swimming for up to 120 min. The level of hepatic PEPCK mRNA increased progressively during exercise, reaching 510% above control, whereas transcription of the PEPCK gene increased 1,000%, before decreasing to control levels within 60 min of recovery. In transgenic mice carrying a chimeric gene consisting of the PEPCK promoter linked to a reporter gene for bovine growth hormone (bGH), PEPCK(-460)-bGH, the level of hepatic bGH mRNA increased by 490% in response to exercise, similar to the increase in the expression of the native PEPCK gene. However, in transgenic mice with a deletion of the glucocorticoid regulatory unit, PEPCK(-355)-bGH, bGH mRNA did not increase above control values. In transgenic mice with a block mutation in adenosine 3',5'-cyclic monophosphate (cAMP) regulatory regions -90/-82 and -250/-234, PEPCK cAMP response element 1 (CRE-1)/P3(1)-bGH, exercise increased bGH mRNA 260% above controls. Adrenalectomy (Adx) had no effect on PEPCK mRNA levels in nonexercised mice, whereas in adrenalectomized (Adx)-exercised mice, PEPCK mRNA increased only 80% above basal, and, in Adx mice injected with dexamethasone, PEPCK mRNA increased with exercise 570% above controls. Exercise was also associated with a large increase in transcription of the gene for the transcription factor CCAAT/enhancer-binding protein beta (C/EBP-beta) and a smaller rise in transcription of c-jun gene, both of which returned to control levels during recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
Multihormonal regulation of phosphoenolpyruvate carboxykinase gene transcription. The dominant role of insulin
