Study Links Inosine to Increased Fat Burning

Researchers in Germany have identified inosine as a key molecule for fat burning and shown that an existing drug inhibiting transport of the molecule—lowering extracellular availability—could be an effective treatment for obesity.

Normally, fat cells store energy. In brown fat cells, however, energy is dissipated as heat, making brown fat a biological heater. This is a mechanism most mammals have; in humans, it keeps newborns warm and boosts metabolism in adults.

However, changes to lifestyles have reduced the amount of brown fat cells a human body has. "Nowadays… we're toasty warm even in winter," says Professor Dr. Alexander Pfeifer of the University of Bonn’s Institute of Pharmacology and Toxicology. "So our body's own furnaces are hardly needed anymore." Our more energy-dense diets and sedentary routines compared to our ancestors have also contributed to brown fat cells ceasing to function and eventually die.

At the same time, the number of severely overweight people worldwide continues to increase. "Research groups around the world are therefore looking for substances that stimulate brown fat and thus increase fat burning," says Pfeifer.

Toward this end, Pfeifer and colleagues set out to study brown fat cells subjected to severe stress, so that the cells were virtually dying. "It is known that dying cells release a mix of messenger molecules that influence the function of their neighbors," says Dr. Birte Niemann. "We wanted to know if this mechanism also exists in brown fat."

They found that brown fat secretes the purine inosine in large quantities when subjected to stress. More interesting, however, was how intact brown fat cells responded to the molecular call for help: They were activated by inosine, or simply by dying cells in their vicinity. Inosine thus fanned the furnace inside them, and also caused white fat cells to convert to brown.

Notably, mice fed a high-energy diet and treated with inosine at the same time remained leaner compared to control animals and were protected from diabetes.

The inosine transporter seems to play an important role in this context. This cell membrane protein transports inosine into the cell, thus lowering extracellular concentration. Therefore, inosine can no longer exert its combustion-promoting effect.

"There is a drug that was actually developed for coagulation disorders, but also inhibits the inosine transporter," says Pfeifer, who is also a member of the Transdisciplinary Research Areas "Life and Health" and "Sustainable Futures" at the University. "We gave this drug to mice, and as a result they burned more energy."

Humans also have an inosine transporter. In 2­–4% of people, it is less active due to a genetic variation. "Our colleagues at the University of Leipzig have genetically analyzed 900 individuals," Pfeifer explains. "Those subjects with the less active transporter were significantly leaner on average." These results suggest that inosine also regulates thermogenesis in human brown fat cells.

"However, further studies in humans are needed to clarify the pharmacological potential of this mechanism," Pfeifer says. Neither does he believe that a pill alone will be the solution to the world's rampant obesity pandemic. "But the available therapies are not effective enough at the moment," he stresses. "We therefore desperately need medications to normalize energy balance in obese patients."

The findings were published recently in Nature. The University Hospital Bonn, University Medical Center Hamburg-Eppendorf, University of Leipzig, University Hospital Leipzig, Helmholtz Center Munich and University of Texas were also involved in the study.