The Cellular Impact of Diet and Exercise
Massachusetts Institute of Technology (MIT) and Harvard Medical School researchers recently studied the nitty-gritty of how diet and exercise impact the body. This rodent* study lays out all the cells, genes, and cellular paths impacted by exercise or a high-fat diet. Their discoveries could result in possible drug targets that help enhance or copy the benefits of exercise.
Manolis Kellis, a professor of computer science in MIT's Computer Science and Artificial Intelligence Laboratory (CSAIL) and a member of the Broad Institute of MIT and Harvard notes, "It is extremely important to understand the molecular mechanisms that are drivers of the beneficial effects of exercise and the detrimental effects of a high-fat diet, so that we can understand how we can intervene, and develop drugs that mimic the impact of exercise across multiple tissues.”
Mice were divided into two groups receiving either high-fat or normal diets. They were either inactive or given the chance to exercise whenever they desired. The researchers used single-cell RNA sequencing and tracked the activity of 53 cell types found in skeletal muscle and two types of fat tissue. "One of the general points that we found in our study, which is overwhelmingly clear, is how high-fat diets push all of these cells and systems in one way, and exercise seems to be pushing them nearly all in the opposite way," Kellis says. "It says that exercise can really have a major effect throughout the body."
Combating Obesity
In the US, over 40% of the population falls in the obese category, with almost 75% overweight. Being overweight or obese raises the risk for several chronic diseases including cancer, diabetes, heart disease, Alzheimer’s disease, and also COVID-19. Obesity and aging are global factors that impact human health, notes Kellis.
In 2015, Kellis’ lab did a study on the fat mass and obesity-associated (FTO) gene region, which is linked with the risk for obesity. His team discovered that genes in this region control a system that prompts young fat cells, known as progenitor adipocytes, to become either fat-burning or fat-storing cells. This finding showed a clear genetic link to obesity.
Kellis started to look at how exercise could prevent obesity as a well-known behavioral intervention. He wanted to see how exercise could act on progenitor adipocytes at the cellular level. Through more experimentation, Kellis and his team performed single-cell RNA sequencing on three types of tissue, including skeletal and visceral (surrounding internal organs) white adipose tissue and subcutaneous (under the skin) white tissue that burns fat.
In the study, tissues from mice in four experimental groups were evaluated. Two groups of mice were fed either a high-fat or a normal diet for three weeks. The other two groups were further split into a sedentary group and an exercise group with regular treadmill access. The researchers then cataloged the genes based on activation or suppression by exercise in 53 different cell types.
In all three tissues, mesenchymal stem cells (MSCs) were found to control several diet and exercise-induced effects. MSCs are stem cells that can change into other cell types, including fat cells and fibroblasts. In fat tissue, the scientists found that a high-fat diet altered MSC’s ability to differentiate into fat-storing cells, while exercise reversed the effect.
Along with enhancing fat storage, the scientists discovered that a high-fat diet also increased MSCs to secrete factors that changed the extracellular matrix (ECM). ECM is defined as a collection of proteins and other structures that surround and support tissues and cells inside the body. The ECM remodeling assists in providing structure for large fat-storing cells and makes a more inflammatory environment.
"As the adipocytes become overloaded with lipids, there's an extreme amount of stress, and that causes low-grade inflammation, which is systemic and preserved for a long time," Kellis says. "That is one of the factors that is contributing to many of the adverse effects of obesity."
Circadian Impact
Kellis and his group discovered that high-fat diets and exercise had opposite effects on cellular tracks that impact circadian rhythms -- the 24-hour cycles that affect many functions including sleep, body temperature, hormone release, and digestion. The study showed that exercise enhances the expression of genes that regulate these rhythms, and a high-fat diet dampens them.
"There have been a lot of studies showing that when you eat during the day is extremely important in how you absorb the calories," Kellis says. "The circadian rhythm connection is a very important one, and shows how obesity and exercise are in fact directly impacting that circadian rhythm in peripheral organs, which could act systemically on distal clocks and regulate stem cell functions and immunity."
Results were compared to a human gene database that’s been linked with metabolic traits. They discovered that two of the circadian rhythm genes found in this study called, “CBP and CDKN1A” have genetic variants that are linked to a higher risk of obesity and humans. "These results help us see the translational values of these targets, and how we could potentially target specific biological processes in specific cell types," Yang says.
The group is now evaluating samples of the small intestine, liver, and brain tissue from the mice in this study, to evaluate the effects of high-fat diets and exercise on these tissues. Research is also done on human volunteers to sample blood and biopsies to look at the similarities and differences between human and mouse physiology. Their hope is that their findings will help guide drug development in creating drugs that mimic some of the helpful effects of exercise.
“The take-home message is to eat healthier and get regular exercise if you’re able,” Kellis says. "For those for whom this is not possible, due to low access to healthy foods, or due to disabilities or other factors that prevent exercise, or simply lack of time to have a healthy diet or a healthy lifestyle, what this study says is that we now have a better handle on the pathways, the specific genes, and the specific molecular and cellular processes that we should be manipulating therapeutically."
What Tips Can Health Professionals Give Their Clients?
Add more fruits, vegetables, whole grains, beans, nuts, and seeds to your diet.
Reduce high-fat meat and dairy products.
Include exercise “snacks” throughout the day such as 3 to 5-minute walks every hour.
Reduce fast food and fried foods to cut fat from your diet.
Include resistance training exercises to aid in fat burning.
Keep tennis shoes in your car so you can go for a walk
Choose smaller serving sizes to aid in weight control.
By Lisa Andrews, MEd, RD, LD
Reference:
Yang, J., Vamvini, M., Nigro, P., Ho, L.-L., Galani, K., Alvarez, M., Tanigawa, Y., Renfro, A., Carbone, N. P., Laakso, M., Agudelo, L. Z., Pajukanta, P., Hirshman, M. F., Middelbeek, R. J. W., Grove, K., Goodyear, L. J., & Kellis, M. (2022). Single-cell dissection of the obesity-exercise axis in adipose-muscle tissues implies a critical role for mesenchymal stem cells. Cell Metabolism, 34(10). https://doi.org/10.1016/j.cmet.2022.09.004
* Mouse