Study reveals molecular pathway by which intense exercise promotes weight loss
Boosting the activity of one gene in the muscles of mice powerfully enhances their ability to lose weight with fasting.
November 08, 2021
JUPITER, FL—When you try to lose weight by eating less, your body tends to resist by slowing its metabolism and ramping up the hunger pangs. This is why diets fail so often. But people who maintain long-term weight loss almost invariably exercise, and a new study from scientists at Scripps Research reveals key molecular details of this weight loss-enhancing effect.
The researchers, who report their findings in the FASEB (Federation of American Societies for Experimental Biology) Journal, engineered mice to overexpress a gene called CRCT2. This gene is among those activated by intense or new exertion, and it is known to account for many of the fitness benefits of high-intensity interval workouts.
The scientists found that by boosting CRCT2 they also could powerfully counter the metabolism-slowing, hunger-boosting effects of fasting in mice, allowing the animals to lose more weight compared to mice who lacked the extra CRCT2 activity.
“Just by manipulating this one gene we were able to reproduce weight-loss benefits of high intensity interval training, including the maintenance during fasting of a higher metabolic rate, greater loss of fat mass, and greater resistance to the loss of muscle mass,” says study senior author Kendall Nettles, PhD, associate professor in the Department of Integrative Structural and Computational Biology at Scripps Research in Florida.
The benefits of stress
Surveys by the U.S. Centers for Disease Control suggest that about 70 percent of Americans qualify as overweight or obese, reflecting one of the most striking and worrisome health trends of modern times. Overweight and obesity are associated with elevated risks of a long list of disorders, from diabetes to cardiovascular disease. Thus there is a particular urgency to the study of the biology of weight gain and weight loss.
In a 2014 study, Scripps Research investigators including Nettles detailed how CRCT2 is activated downstream of the surge of the stress hormone norepinephrine, which occurs when intense exercise triggers the “fight or flight” stress response. The researchers engineered mice in which they could switch on CRCT2 activity in muscles at much higher levels than normal, and found that this relatively simple genetic juicing of the mice quickly reproduced the strength and performance benefits of intense exercise, giving them bigger muscles and exercise capacity.
“It was quite amazing,” Nettles says. “Imagine being able to ride a bike at 10 miles an hour for an hour, and then just a week later being able to ride at 20 miles an hour for two hours—that was the degree of the performance enhancement we saw in these mice.”
In the new study, the researchers examined CRCT2’s exercise-like impact in the context of dieting. Prior studies have shown that exercise is very important for sustaining weight-loss when dieting. Exercise doesn’t just directly burn calories. It also, among other effects, raises the background calorie-burning rate, countering the metabolic slowing that normally occurs with lowered food intake.
The scientists found this same “exercise effect” in mice whose muscles had overactive CRCT2. Over two weeks of an alternate-day fasting regimen, the high-CRCT2 mice lost twice as much weight as normal-CRCT2 mice while maintaining a higher rate of metabolism and showing less binge eating when food was available. The high-CRCT2 mice also lost mainly fat, whereas the normal mice lost mostly lean mass—which is to say, mostly muscle.
Apart from illuminating these exercise-activated pathways, the research also made clear that the stress hormone norepinephrine has a more complex role than has traditionally been assumed.
“We’ve thought of the stress hormones norepinephrine and epinephrine (also known as noradrenaline and adrenaline) as being released during intense or new exercise to help break down fat and other molecules in the short term for use as fuel,” Nettles says. “We haven’t thought about them as regulators of long-term metabolism and muscle-building—so that’s a big change.”
Developing a drug, for example a future obesity or diabetes drug, that boosts CRCT2 as the researchers did in this study, is somewhat problematic, Nettles says. An existing drug that has this effect is considered an illicit performance-enhancer and is not approved for any human use in the United States because of its adverse side effects, which include heart palpitations and muscle tremors.
“This research suggests that exercise that releases these stress hormones, such as with high intensity or switching your routine will improve maintenance of weight loss, Nettles says.
In addition to Nettles, authors of “Activation of Crtc2/Creb1 in skeletal muscle enhances weight loss during intermittent fasting” include Nelson Bruno, Jerome Nwachukwu, Sathish Srinivasan, Richard Hawkins and Michael Conkright of Scripps Research; David Hughes, and Sue Bodine of the University of Iowa; David Sturgill and Gordon Hager of the National Cancer Institute; and Stephen Hurst and Shey-Shing Sheu of Thomas Jefferson University.
For more information, contact press@scripps.edu