Down-regulation of hepatic AMP-activated protein kinase and up-regulation of CREB coactivator CRTC2 for gluconeogenesis under calorie-restricted conditions at a young age

AMP-activated protein kinase (AMPK) is a key molecule that controls energy homeostasis at cellular and whole body levels. Calorie restriction (CR) may exhibit the anti-aging effect through modulation of AMPK activity. We investigated the hepatic AMPK pathways for gluconeogenesis (the transducer of regulated cyclic adenosine monophosphate response element-binding protein (CREB) 2; CRTC2) and cell growth (mammalian target of rapamycin, mTOR). Male F344 rats at 2.5 months (mo) and 18 mo of age were subjected to 4-mo-long 30% CR; control rats were fed ad libitum (AL) throughout the experiment. Rats were killed 15 min after saline or glucose injection to evaluate activation of signal molecules under transient hyperglycemic and subsequent hyperinsulinemic conditions. Western blot analyses demonstrated a modest reduction of threonine-172-phosphorylated (p)-AMPKα levels and an increment of nuclear CRTC2 in the young CR group as compared with the agematched AL group. We also confirmed the increased binding of CRTC2 and CREB and up-regulation of gluconeogenic genes (PGC-1α and PEPCK) in the CR group. However, there was no CR-specific alteration in total or phosphorylated mTOR levels. The results suggest down-regulation of hepatic AMPK activity by CR for metabolic adaptation that promotes gluconeogenesis. The effect of CR on mTOR remains elusive