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Low sugar/fat may increase fat metabolism and exercise endurance in mice

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Loss of a specific enzyme increases fat metabolism and exercise endurance in mice

when nutrients are scarce, such as during starvation or extreme exertion, cells will switch to breaking down fats

new research reveals a surprising consequence when one such mechanism is turned off: an increased capacity for endurance exercise.

researchers identified a critical role of the enzyme, prolyl hydroxylase 3 (PHD3), in sensing nutrient availability and regulating the ability of muscle cells to break down fats. When nutrients are abundant, PHD3 acts as a brake that inhibits unnecessary fat metabolism. This brake is released when fuel is low and more energy is needed, such as during exercise.

blocking PHD3 production in mice leads to dramatic improvements in certain measures of fitness, the research showed. Compared with their normal littermates, mice lacking the PHD3 enzyme ran 40 percent longer and 50 percent farther on treadmills and had higher VO2 max

under normal conditions, PHD3 chemically modifies another enzyme, ACC2, which in turn prevents fatty acids from entering mitochondria to be broken down into energy.

the researchers' experiments revealed that PHD3 and another enzyme called AMPK simultaneously control the activity of ACC2 to regulate fat metabolism, depending on energy availability.

In isolated mouse cells grown in sugar-rich conditions, the team found that PHD3 chemically modifies ACC2 to inhibit fat metabolism. Under low-sugar conditions, however, AMPK activates and places a different, opposing chemical modification on ACC2, which represses PHD3 activity and allows fatty acids to enter the mitochondria to be broken down for energy.

These observations were confirmed in live mice that were fasted to induce energy-deficient conditions.

In addition, Haigis and colleagues found in previous studies that in certain cancers, such as some forms of leukemia, mutated cells express significantly lower levels of PHD3 and consume fats to fuel aberrant growth and proliferation. Efforts to control this pathway as a potential strategy for treating such cancers 

It remains unclear whether there are any negative effects of PHD3 loss. To know whether PHD3 can be manipulated in humans—for performance enhancement in athletic activities or as a treatment for certain diseases —will require additional studies in a variety of contexts, the authors said.

It also remains unclear if PHD3 loss triggers other changes, such as weight loss, blood sugar and other metabolic markers, which are now being explored by the team.

 

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