How Muscle, Fat Tissues Respond to Exercise, Obesity – Harvard Medical School


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Exercise training is a well-known means of maintaining and restoring good health. However, the molecular mechanisms underlying the benefits of exercise are not yet completely understood.
A new paper by researchers at Harvard Medical School and Joslin Diabetes Center in Cell Metabolism sheds light on the complex physiological response to exercise found in mice.
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Taking advantage of recent single-cell technologies and advancements in computational biology, a team led by co-author Laurie Goodyear, HMS professor of medicine at Joslin and senior investigator of Integrative Physiology and Metabolism at Joslin Diabetes Center, launched a collaboration with a computational biology and artificial intelligence lab at MIT led by co-author Manolis Kellis to investigate how three metabolic tissues respond to exercise and to high-fat diet-induced obesity at single-cell resolution.
These first-of-their-kind results provide a reference atlas of the single-cell changes induced by exercise and obesity in two different types of fat and muscle.
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The investigators found opposite responses to exercise and obesity across all three tissues and that the responses highlight prominent molecular pathways modulated by exercise and obesity.
“Regular physical exercise is a well-established intervention for prevention and treatment of obesity and diabetes, and our goal is to set the foundation for understanding the molecular changes and cell types mediating the systemic effects of exercise and obesity in different tissues throughout the body,” said Goodyear.
“The results of this study are going to serve as a tremendous resource that can lead to so much other work – not just from our laboratory but from other labs, too – that could eventually lead to the discovery of novel therapeutic options for obesity and other chronic metabolic diseases,” she said.
Goodyear and colleagues focused the investigation on two kinds of white adipose tissue, or fat, and skeletal muscle taken from mice, either trained or sedentary, and fed either a healthful chow diet or a high-fat diet intended to mimic the typical Western diet.
This effectively resulted in four groups of mice; chow-fed/sedentary, chow-fed/active, HFD/sedentary and HFD/active.
Diet treatments occurred over six weeks, and exercise training was done by housing mice with free access to a running wheel for three weeks.
After three weeks of the exercise intervention, the animals’ tissues were analyzed with single-cell RNA sequencing, providing the researchers with a plethora of new data.
Among the most striking findings, the scientists observed that genes governing extracellular modeling and circadian rhythm were regulated by both exercise and obesity across all three tissue types.
Obesity upregulated extracellular modeling-related pathways, while exercise downregulated them. Conversely, exercise upregulated circadian-related pathways, and obesity downregulated them.
“With respect to the circadian rhythm, we saw very quiet cells that weren’t metabolically active with the high-fat diet group,” said co-first author Pasquale Nigro, HMS instructor in medicine at Joslin.
“We discovered that exercise reversed this. It seemed that, when the circadian system is upregulated, cells become reactivated,” Nigro said.
“As one of the most effective strategies to maintain a healthy body and mind, exercise is increasingly understood to induce tissue-specific and shared adaptations in the context of many other diseases beyond obesity,” said co-first author Maria Vamvini, HMS instructor in medicine at Joslin.
“By combining our knowledge as physiologists with the computational biology skills of the Kellis lab at MIT, we’ve been able to develop a single-cell atlas with more than 200,000 cells and 53 annotated cell types,” she said.
“This resource has the potential to help our research team as well as others reveal fundamental exercise-induced changes in a diverse set of diseases and physiological contexts such as cancer and aging. This teamwork stands out as a model for what we can accomplish through collaboration.”
Co-authors included Jiekun Yang, Li-Lun Ho, Kiki Galani, Yosuke Tanigawa, Ashley Renfro, and Leandro Agudelo, Nicholas Carbone, Michael F. Hirshman and Roeland J. W. Middelbeek, Marcus Alvarez, Päivi Pajukanta, Markku Laasko, and Kevin Grove.
This work was supported by Novo Nordisk Research Center; the National Institutes of Health (R01D K 099511, 5P30-DK-36836, U24HG009446, UG3NS115064, T32-DK110919, T32-DK007260, F32-DK126432, K23-DK14550, R01HG008155, R01AG067151, R01HG010505, R01DK132775); and Joslin Diabetes Center P&F.
Grove is an employee of Novo Nordisk. All other authors report no conflicts of interest.
Adapted from a Joslin news release.
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