Apoptotic brown adipocytes stimulate surrounding healthy cells by the release of purine metabolite
A study led by ImmunoSensation2 member Prof. Alexander Pfeiffer at the University Hospital Bonn identified a molecule - the purine inosine - that boosts fat burning in brown adipocytes. The mechanism was discovered in mice, but probably exists in humans as well: If a transporter for inosine is less active, the mice remain significantly leaner despite a high-fat diet. The study, which also involved researchers from the University of Leipzig and the University Medical Center Hamburg-Eppendorf, has now been published in the journal Nature.
In human adults, brown adipocyte activation positively correlates with cardio-metabolic health. While white adipocytes store energy, brown adipocytes dissipate energy as heat and thereby act a biological heater.
"Nowadays, however, we're toasty warm even in winter," explains Prof. Dr. Alexander Pfeifer from the Institute of Pharmacology and Toxicology at the University Hospital Bonn. "So our body's own furnaces are hardly needed anymore." At the same time, we are eating an increasingly energy-dense diet and are also moving far less than our ancestors. These three factors are poison for brown fat cells: They gradually cease to function and eventually even die. On the other hand, 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.
Apoptotic adipocytes boost energy combustion of their neighbors
Together with a group of colleagues, the team at the University of Bonn has now identified the purine metabolite inosine to stimulate the fat burning in neighboring adipocytes. "It is known that dying cells release a mix of messenger molecules that influence the function of their neighbors," explains Dr. Birte Niemann from Pfeifer's research group. Together with her colleague Dr. Saskia Haufs-Brusberg, she planned and conducted the central experiments of the study. "We wanted to know if this mechanism also exists in brown fat."
The researchers therefore studied brown adipocytes subjected to severe stress, so that the cells were virtually dying. "We found that they secrete the purine inosine in large quantities," Niemann says. More interesting, however, was how intact brown adipocytes responded to the molecular stimulus: They were activated by inosine (or simply by dying cells in their vicinity). White fat cells also converted to their brown siblings. Strikingly, 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.
Inosine transporter as potential drug target?
The inosine transporter, shuttling inosine from the extracellular space into the cytosol, seems to play an important role in the context of inosine-mediated regulation of brown adipocyte activity: By decreasing the extracellular inosine concentration, it contributes to diminishing the combustion-promoting effect. Blocking the receptor could hence prolong the positive effect of inosine on fat burnng. "There is a drug that was actually developed for coagulation disorders, but also inhibits the inosine transporter," says Pfeifer. "We gave this drug to mice, and as a result they burned more energy." Humans also have an inosine transporter. In two to four percent of all 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 adipocytes. Substances that interfere with the activity of the transporter could therefore potentially be suitable for the treatment of obesity. The drug already approved for coagulation disorders could serve as a starting point. "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."
Funding
The University of Bonn as well as the University Hospital Bonn, the University Medical Center Hamburg-Eppendorf, the University as well as the University Hospital Leipzig, the Helmholtz Center Munich and the University of Texas were involved in the study. The work was funded by the German Research Foundation and the National Institute of Health (USA).
Publication
Birte Niemann et al.: Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine; Nature; https://doi.org/10.1038/s41586-022-05041-0
Contact
Institute of Pharmacology and Toxicology
University of Bonn
Phone: +49 228 28751300
