Exercise causes many body tissues to undergo beneficial adaptations that contribute to improved metabolic health. Studies headed by a team at Ohio State University Wexner Medical Center now indicate that some of these beneficial effects may be mediated, at least in part, by a circulating lipid hormone, or lipokine, which is released by brown fat in response to exercise.

Kristin Stanford, Ph.D., and colleagues found that humans and mice who completed just a single bout of moderate exercise exhibited much higher circulating blood levels of the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). Further tests in mice showed that the lipokine was released by brown adipose tissue (BAT) and caused skeletal muscles to increase their uptake and metabolism of fatty acids, but not glucose.

“We know that exercise is great for metabolism, but we don't fully understand why that is on a cellular level,” says Dr. Stanford, a researcher at Ohio State’s Diabetes and Metabolism Research Center, and an assistant professor of physiology and cell biology. “This study shows that burning of brown fat and this lipid in particular likely play an important role.”

The Ohio State team, along with collaborators at Joslin Diabetes Center and Harvard Medical School, report their findings in Cell Metabolism, in a paper entitled “12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake.”

There is growing scientific interest in whether circulating factors released by tissues during exercise might mediate some of the many health benefits of regular physical activity. Research has focused on muscle-derived factors, but the potential role of other factors, such as adipokines is also being investigated.

Lipokines are a recently identified class of lipids that act as signaling molecules and can influence systemic metabolism. A prior study by the Ohio State team has shown that exposure to cold leads to increased circulating levels of the linoleic acid metabolite 12,13-diHOME, and that increased levels of the lipid are linked with improved metabolic health. What hasn’t been investigated is whether exercise can have a direct effect on circulating signaling lipokines.

To answer this question, the Ohio State team and colleagues measured blood lipokine levels in 56 human volunteers after they had undertaken a moderate session of exercise either on a static bicycle, or on a treadmill. Men and women of all ages, including those who were normally sedentary and normally active, participated. The results showed that blood levels of just one lipokine, 12,13-diHOME, were significantly raised after exercise, irrespective of gender, age, or usual level of physical activity. “One lipokine just shot right up to the top,” Stanford says.

Further studies in mice confirmed the animals also exhibited increased blood levels of 12,13-diHOME as a result of exercise. However, after surgical removal of BAT, the animals no longer showed exercise-induced increase in the lipokine, indicating that BAT was the source of the circulating 12,13-diHOME. Additional tests in rodents showed that administering 12,13-diHOME directly led to increased fatty acid uptake and oxidation—but not increased glucose uptake—by skeletal muscle.

The results from  analyses of human muscle fibers showed that increased circulating levels of 12,13-diHOME correlated with increased capacity for mitochondrial respiration in skeletal muscle and increased maximal respiratory capacity in myotubes. This raises the possibility that exercise-related elevation in circulating 12,13-diHOME might increase the respiratory capacity of working skeletal muscle and enhance exercise capacity, the authors suggest. “This will be an interesting question for future investigation,” they write.

Prior research by the team had shown that both short- and longer-term cold exposure in rodents and humans triggers the release of 12,13-diHome from BAT, and that in response to cold the lipokine functions to decrease circulating triglycerides and promote fatty acid uptake specifically in BAT. “The parallels between the effects of exercise and cold exposure on 12,13-diHOME are striking and somewhat unexpected,” they comment. Cold exposure is a well-known stimulator of BAT activity, but most studies have shown that exercise training decreases BAT activity in humans and rodents. “We propose that cold causes the release of 12,13-diHOME from BAT to function in an autocrine manner to provide fuel for the BAT, whereas exercise causes the release of 12,13-diHOME from BAT to function in an endocrine manner, resulting in stimulation of fatty acids into the working skeletal muscle,” the researchers suggest.

“It's fascinating that rather than burning calories during exercise—which is what occurs with cold exposure—brown fat is functioning to signal the muscle to take up more fatty acids to use as fuel,” comments co-lead author Laurie Goodyear, Ph.D., a researcher at the Joslin Diabetes Center and Harvard Medical School. “During exercise, all the different metabolic tissues, surprisingly including fat tissues, 'talk' to each other, which enables the muscles to use energy, contract, and perform.”

“This shows that these lipokines can be regulated by exercise, and it highlights a new role that brown fat could play in the metabolic benefits of exercise,” adds Dr. Stanford. Future studies will aim to investigate just how 12,13-diHOME works.

The authors do note that research on exercise-induced lipokines shouldn’t be constrained to 12,13-diHOME. Their initial studies had found that while circulating levels of this lipokine were significantly increased immediately after exercise, levels of another 13 lipids were significantly decreased after exercise. Future studies should also aim to investigate the physiological effects of reduced levels of signaling lipids, “…as these factors may play important roles in regulating the metabolic effects of exercise.” 

Previous articleSuperimmune Cell Lines Courtesy of Synthetic Biology
Next articleIncreasing Eye Cells’ Ability to Process Misfolded Proteins May Prevent Retinal Degeneration