Exercise is well known for helping people lose weight and keep it off. However, the identification of the cellular mechanisms underlying this process has been difficult due to the large number of cells and tissues involved.
in a new study in mice that expands researchers’ understanding of how exercise and diet affect the body, researchers at MIT and Harvard Medical School have mapped many of the cells, genes, and cellular pathways that are changed by exercise or high fat diet. The findings could offer potential targets for drugs that could help enhance or mimic the benefits of exercise, the researchers say.
“It is extremely important to understand the molecular mechanisms that drive 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 around the world. multiple tissues,” says Manolis Kellis, a professor of computer science at MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and a fellow at the Broad Institute of MIT and Harvard.
The researchers studied mice on high-fat or normal diets, who were sedentary or given the opportunity to exercise whenever they wanted. Using single-cell RNA sequencing, the researchers cataloged the responses 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 drive all of these cells and systems in one way, and exercise seems to drive almost all of them in the opposite direction.” Kellis says. “He says that exercise can really have a major effect on the entire body.”
Kellis and Laurie Goodyear, a professor of medicine at Harvard Medical School and a principal investigator at the Joslin Diabetes Center, are the lead authors of the study, which appears today in the journal Cellular metabolism. Jiekun Yang, a research scientist at MIT CSAIL; Maria Vamvini, instructor of medicine at the Joslin Diabetes Center; and Pasquale Nigro, an instructor of medicine at the Joslin Diabetes Center, are the lead authors of the article.
The risks of obesity
Obesity is a growing health problem throughout the world. In the United States, more than 40 percent of the population is considered obese and nearly 75 percent is overweight. Being overweight is a risk factor for many diseases, including heart disease, cancer, Alzheimer’s disease, and even infectious diseases like Covid-19.
“Obesity, along with aging, is a global contributing factor to all aspects of human health,” says Kellis.
Several years ago, his laboratory conducted a study in the FTO gene region, which has been strongly linked to obesity risk. In that 2015 study, the research team discovered that genes in this region control a pathway that causes immature fat cells called progenitor adipocytes to become fat-burning cells or fat-storing cells.
That finding, which demonstrated a clear genetic component to obesity, prompted Kellis to begin looking at how exercise, a well-known behavioral intervention that can prevent obesity, might act on adipocyte progenitors at the cellular level.
To explore that question, Kellis and colleagues decided to perform single-cell RNA sequencing of three types of tissue: skeletal muscle, visceral white adipose tissue (found around internal organs, where it stores fat), and white adipose tissue. subcutaneous (which is under the skin and mainly burns fat).
These tissues came from mice from four different experimental groups. For three weeks, two groups of mice received either a normal diet or a high-fat diet. For the next three weeks, each of those two groups was divided into a sedentary group and an exercise group, which had continuous access to a treadmill.
By analyzing tissues from those mice, the researchers were able to comprehensively catalog the genes that were activated or suppressed by exercise in 53 different cell types.
The researchers found that in all three tissue types, mesenchymal stem cells (MSCs) seemed to control many of the diet- and exercise-induced effects they observed. MSCs are stem cells that can differentiate into other cell types, including fat cells and fibroblasts. In adipose tissue, the researchers found that a high-fat diet modulated the ability of MSCs to differentiate into fat-storing cells, while exercise reversed this effect.
In addition to promoting fat storage, the researchers found that a high-fat diet also stimulated MSCs to secrete factors that remodel the extracellular matrix (ECM), a network of proteins and other molecules that surround and support cells and body tissues. This ECM remodeling helps provide structure for the enlarged fat storage cells and also creates a more inflammatory environment.
“As fat cells become overloaded with lipids, there’s an extreme amount of stress and that causes low-grade inflammation, which is systemic and persists for a long time,” says Kellis. “That’s one of the factors that contributes to a lot of the adverse effects of obesity.”
circadian effects
The researchers also found that high-fat diets and exercise had opposing effects on cellular pathways that control circadian rhythms, the 24-hour cycles that govern many functions, from sleep to body temperature to hormone release and metabolism. digestion. The study revealed that exercise increases the expression of genes that regulate these rhythms, while a high-fat diet suppresses them.
“There have been a lot of studies that show that when you eat throughout the day it is extremely important in how you absorb calories,” says Kellis. “The connection with the circadian rhythm is very important and shows how obesity and exercise are, in fact, directly affecting that circadian rhythm in peripheral organs, which could act systemically on distal clocks and regulate stem cell functions.” and immunity.
The researchers then compared their results to a database of human genes that have been linked to metabolic traits. They found that two of the circadian rhythm genes they identified in this study, known as DBP and CDKN1A, have genetic variants that have been associated with an increased risk of obesity in 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,” says Yang.
The researchers are now analyzing small intestine, liver and brain tissue samples from the mice in this study, to explore the effects of exercise and high-fat diets on those tissues. They are also working with human volunteers to take blood samples and biopsies and study the similarities and differences between human and mouse physiology. They hope their findings will help guide drug developers in designing drugs that can mimic some of the beneficial effects of exercise.
“The message to everyone should be to eat a healthy diet and exercise if possible,” says Kellis. “For whom this is not possible, due to low access to healthy foods, or due to disabilities or other factors that prevent them from exercising, or simply due to lack of time to have a healthy diet or a healthy lifestyle, what this says study 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.”
The research was funded by the National Institutes of Health and the Novo Nordisk Research Center in Seattle.
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