When working out, males are programmed to burn more fat, while females recycle it--at least in rats

"Everyone knows that exercise is good for you, but no one knows exactly why," said Joshua Adkins, a scientist at the Department of Energy's Pacific Northwest National Laboratory and a corresponding author of a study published online May 1 in Nature Metabolism. "We don't know what's happening in the body that creates such great benefits."

The results come from the Molecular Transducers of Physical Activity Consortium (MoTrPAC), a years-long study investigating the molecular actions that translate vigorous movement into a glut of health benefits. The collaboration stretches across more than two dozen sites around the country, involving more than 100 scientists.

The group published its core paper in the journal Nature on May 1, finding that the effects of exercise are extensive, affecting more than 35,000 molecules. No tissue studied goes unchanged.

The study subjects were rats, which share much of their basic physiology with people. This group of scientists is now studying more than 1,500 people, using the findings from rats as a starting point to investigate what happens in humans.

Overall, the MoTrPAC team looked at 18 tissue types as well as blood. They found molecular signals in both males and females that demonstrated extensive benefits of exercise: enhanced liver function, stronger heart muscle, enriched immunity, and reduced inflammation in the lungs and gut. Throughout the body, cellular organelles known as mitochondria -- the energy producers in cells -- become healthier after exercise.

The most remarkable difference between the sexes was in the fat tissue, the subject of the Nature Metabolism paper.

"We found that fat tissue between males and females is very different even in sedentary animals," said Christopher Newgard, a corresponding author and director of the Duke Molecular Physiology Institute. "But then I was truly gobsmacked with how amazingly different the sex-dependent responses to exercise are. Males burn fat for energy while females preserve their fat mass. This is brought about by many differences in molecular responses lurking beneath the surface in fat from male compared to female rats. The dichotomy is truly striking."

In addition to Adkins and Newgard, corresponding authors of the Nature Metabolism paper are Sue Bodine of the Oklahoma Medical Research Foundation and Simon Schenk of the University of California San Diego. The paper has three "first authors" from PNNL: Gina Many, James Sanford and Tyler Sagendorf.

Findings from rats on the run

The results are based on an analysis of tissues and blood samples from rats that ran on treadmills in a research laboratory at the University of Iowa. The team made thousands of measurements of proteins, molecular messengers known as transcripts, and chemical compounds called metabolites. Those measurements give scientists clues about what's actually happening in the body. Behind every breath, thought, movement or step on a treadmill, there's a cascade of molecular actions that make things happen and affect the body.

The samples were sent to several laboratories for analysis. Scientists at PNNL analyzed the proteins in the fat samples -- a challenging task because fat has few proteins relative to lipids. The team looked at white adipose tissue, by far the most prevalent form of fat in the body.

Scientists studied rats that ran five days a week for one, two, four or eight weeks, comparing them to sedentary rats. The team studied healthy, lean animals. The scientists note that the study's finding can't be automatically applied to animals that are obese, for instance, or to other types of exercises, such as strength training.

Less fat, same amount of fat, healthier fat

The difference in fat characteristics was remarkable even between male and female rats that were sedentary. More than 20,000 molecular measures were different. Overall, the fat in female rats was healthier both before and after training.

Male and female sedentary rats did have one characteristic in common: They all gained weight throughout the study.

The differences in rats that ran the treadmill were even more noteworthy. Males burned fat and kept it off. Females initially burned fat, but by the end of eight weeks, their fat stores were back to where they were when they started. Male rats that exercised lost fat. Female rats that exercised did not lose fat -- but they did not gain fat as their sedentary counterparts did.

Exercise did make the fat stores of both sexes healthier -- more metabolically active and energetic, with fewer signals like those involved in obesity. This was more noteworthy in the male rats, whose fat was less healthy to start.

"We saw both sexes mobilize their metabolism to get the energy they need," said first author Gina Many. "But they get their energy in different ways. Females do so without drawing much from their fat stores, likely because those are critical to reproductive health."

In recent decades, scientists have learned that fat isn't simply a blob of unwelcome weight. It's a major organ that runs throughout our body, like the skin, that secretes hormones and other compounds that play an important role in our health. Fat is a font of both health and disease.

A road map from rats to people

"These findings help set the landscape to understand disease risk and establish a basis for more personalized and targeted health interventions," said Many.

The investigators said the results make it crucial that health studies include women and men, noting that when it comes to exercise, many more men than women have been studied.

"This study really opened my eyes," said Newgard. "The differences between the sexes are much more vast than I would have anticipated. This is changing the way I am approaching other studies, including one on insulin resistance in males and females. These findings provide a road map for those experiments."

The MoTrPAC study is funded by the National Institutes of Health Common Fund. Many of the protein analyses discussed in the Nature Metabolism paper were done at the Environmental Molecular Sciences Laboratory, a DOE Office of Science user facility on the PNNL campus. The technologies used by the PNNL team in the MoTrPAC experiment are also used to explore molecular reactions important to climate, energy and the environment.