  The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic
regulator that mediates adaptation to nutritional variations in order to
maintain a proper energy balance in cells. We show here that suckling-weaning
and fasting-refeeding transitions in rodents are associated with changes in
AMPK activation and the cellular energy state in the liver. These nutritional
transitions were characterized by a metabolic switch from lipid to glucose
utilization, orchestrated by modifications in glucose levels and the
glucagon:insulin ratio in the bloodstream. We therefore investigated the
respective roles of glucose and pancreatic hormones on AMPK activation in mouse
primary hepatocytes. We found that glucose starvation transiently activates
AMPK, whereas changes in glucagon and insulin levels had no impact on AMPK.
Challenge of hepatocytes with metformin-induced metabolic stress strengthened
both AMPK activation and cellular energy depletion limited-glucose conditions,
whereas neither glucagon nor insulin altered AMPK activation. Although both
insulin and glucagon induced AMPK$\alpha$ phosphorylation at its Ser-485/491
residue, they did not affect its activity. Finally, the decrease in cellular
ATP levels in response to an energy stress was additionally exacerbated under
fasting conditions and by AMPK deficiency in hepatocytes, revealing metabolic
inflexibility and emphasizing the importance of AMPK for maintaining hepatic
energy charge. Our results suggest that nutritional changes (i.e. glucose
availability), rather than the related hormonal changes (i.e. the
glucagon:insulin ratio), sensitize AMPK activation to the energetic stress
induced by the dietary transition during fasting. This effect is critical for
preserving the cellular energy state in the liver.
