  To sustain metabolism, intracellular ATP concentration must be regulated
within an appropriate range. This coordination is achieved through the function
of the AMP-activated protein kinase (AMPK), a cellular "fuel gauge" that is
expressed in essentially all eukaryotic cells as heterotrimeric complexes
containing catalytic $\alpha$ subunits and regulatory $\beta$ and $\gamma$
subunits. When cellular energy status has been compromised, AMPK is activated
by increases in AMP:ATP or ADP:ATP ratios and acts to restore energy
homeostasis by stimulating energy production via catabolic pathways while
decreasing non-essential energy-consuming pathways. Although the primary
function of AMPK is to regulate energy homeostasis at a cell-autonomous level,
in multicellular organisms, the AMPK system has evolved to interact with
hormones to regulate energy intake and expenditure at the whole body level.
Thus, AMPK functions as a signaling hub, coordinating anabolic and catabolic
pathways to balance nutrient supply with energy demand at both the cellular and
whole-body levels. AMPK is activated by various metabolic stresses such as
ischemia or hypoxia or glucose deprivation and has both acute and long-term
effects on metabolic pathways and key cellular functions. In addition, AMPK
appears to be a major sensor of energy demand in exercising muscle and acts
both as a multitask gatekeeper and an energy regulator in skeletal muscle.
Acute activation of AMPK has been shown to promote glucose transport and fatty
acid oxidation while suppressing glycogen synthase activity and protein
synthesis. Chronic activation of AMPK induces a shift in muscle fiber type
composition, reduces markers of muscle degeneration and enhances muscle
oxidative capacity potentially by stimulating mitochondrial biogenesis.
Furthermore, recent evidence demonstrates that AMPK may not only regulate
metabolism during exercise but also in the recovery phase. AMPK acts as a
molecular transducer between exercise and insulin signaling and is necessary
for the ability of prior contraction/exercise to increase muscle insulin
sensitivity. Based on these observations, drugs that activate AMPK might be
expected to be useful in the treatment of metabolic disorders and insulin
resistance in various conditions.
