Understanding how cells switch between anabolic and catabolic states
University of Michigan researchers have illuminated a critical transaction involved with the way cells sense and regulate energy, pointing the way toward possible new therapeutics for metabolic disorders.
In a paper published April 25 in Molecular Cell, Life Sciences Institute faculty member Ken Inoki reported that multiple signaling pathways act in concert to inhibit the action of the key regulatory protein called AMPK, which plays a prominent role in making sense of multiple energy-related signals within the cell and switching between consuming and producing energy.
Healthy cells maintain a balance between the “building” phase, or anabolism, and “taking apart” or burning phase, called catabolism. But in disorders like obesity, the body’s balance is tipped toward an anabolic state. Increasing catabolism—burning more energy—is one possible way to restore the balance. However, the mechanism by which a cell switches from anabolic to catabolic states is largely unknown.
AMPK, for “AMP-activated protein kinase,” lies at the center of many energy-related pathways and is responsible for switching the cell from anabolic to catabolic states in response to energy levels within the cell. Enhancement of AMPK activity is a promising therapeutic strategy for metabolic disorders because its catabolic activity lowers blood glucose and burns lipids.
Inoki found that a molecule called GSK3, which is involved a wide range of intercellular processes, inhibits AMPK and so inhibits the catabolic process.
“We assumed there was a lot of crosstalk between these pathways, but didn’t know exactly how they interacted,” Inoki said.
They found that GSK3 played a critical role in inhibiting AMPK by interacting with a very specific part of the protein, and—unexpectedly—the GSK3 inhibitory activity in the AMPK complex was enhanced by the insulin signaling. “You would expect that insulin activity would tell GSK3 to stop AMPK burning more energy,” Inoki said.
“We found that disrupting GSK3 function within the AMPK complex sustained higher AMPK activity and catabolic processes—even under anabolic conditions,” Inoki said.
“This was also surprising because GSK3 is a major catabolic kinase in other processes and its activity is normally blocked by insulin action, but in complex with AMPK, GSK3 was anabolic in response to insulin,” Inoki said.
They also proposed that GSK3 changes the shape of AMPK, which ultimately inhibited AMPK activity.
Next, the researchers want to find out what the area actually looks like. “We need to know the structure to confirm our model in future, because the target region of AMPK by GSK3 has never been visualized,” Inoki said.
Ultimately, Inoki said, stimulating AMPK activity by disrupting the interaction between GSK3 and the AMPK complex could have beneficial catabolic effects on metabolic disorders.