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Findings may suggest novel ways to treat metabolic conditions

Cell

Image courtesy of Dr. Marc Montminy and Jamie Simon, Salk Institute for Biological Studies.


By virtue of having survived, all animals—from flies to man—share a common capability. All can distinguish times of plenty from famine and adjust their metabolism or behavior accordingly. Failure to do so signals either extinction or disease.

A collaborative effort by investigators in the labs of Marc Montminy and John Thomas recently revealed just how similarly mammals and insects make critical metabolic adjustments when food availability changes, either due to environmental catastrophe or everyday changes in sleep/wake cycles. Those findings, published in Cell, may suggest novel ways to treat metabolic conditions such as obesity and type 2 diabetes.

In their study, Montminy and Thomas used the fruit fly Drosophila melanogaster to show that activation of a factor called SIK3 by insulin dampens a well-characterized pathway promoting fat breakdown, providing a molecular link between glucose metabolism and lipid storage.

"The metabolic system is like a hybrid car. In the daytime we use glucose as high-octane fuel, but at night we switch to the battery, which in this case is stored fat," says Montminy.

During fasting, a group of fat-busting enzymes, called lipases, trigger the flow of energy from the fly's low-power "battery" fat pack to different organs in the body. These lipases are turned on by a genetic switch, called FOXO, which is part of the central transmission for fasting metabolism. When the flies eat, SIK3 shuts off the FOXO switch, which both cuts off the battery's energy stream by silencing the fat-busting enzymes and allows the fat pack to recharge its batteries.

Unexpectedly, SIK3 does not control the FOXO switch directly. Rather, much like a runner in a relay race, the SIK3 enzyme has to pass the baton to another enzyme, called HDAC4, which in turn regulates FOXO. The investigators found that the SIK3/HDAC4/FOXO machine they characterized in the fruit fly also controls the metabolic hybrid engine in mice.

"Currently, we have over 20 million people with type 2 diabetes and close to 60 million with insulin resistance," says Montminy. "This is a huge problem tied to obesity. Finding a way to curb obesity will essentially require consideration of both environmental and genetic factors. The human counterparts of HDAC4 and SIK3 may be mutated in ways that make them work less effectively and enhance our proclivity to become obese."