Exercise is widely known to aid people in losing weight and prevent it from gaining. But, understanding the cellular processes that drive this process is a challenge due to the fact that a lot of tissues and cells are involved.

In a recent study on mice, which expands the researchers in their understanding of how diet and exercise impact our bodies, MIT as well as Harvard Medical School researchers have traced numerous cells as well as genes and cellular pathways altered by exercise or a diets high in fat. The results could provide drug targets that could assist in increasing or mimicking what benefits exercise can bring the researchers claim.

“It is vital to comprehend the molecular mechanisms that drive the benefits of exercise as well as the harmful consequences of a diet high in fat to determine how we can alter the process and develop medications that mimic the effects of exercise on multiple tissue types,” says Manolis Kellis who is a professor of computer science at the MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) and part of the Broad Institute of MIT and Harvard.

The study focused on mice fed high-fat diets or normal ones that were either sedentary or had the chance to exercise whenever they desired. By using single-cell RNA sequencing the researchers analyzed the responses of 53 different types of cells in skeletal muscles and two types of fat tissue.

“One of the most important aspects we discovered in our research, and which is quite evident, is that the high-fat diets can push all of these systems and cells in one direction, and exercising seems to push them all in the opposite direction,” Kellis says. “It suggests that exercise may actually have a profound effect on the body in general.”

Kellis along with Laurie Goodyear, a professor of medicine at Harvard Medical School and senior researcher in Joslin Diabetes Center. Joslin Diabetes Center, are the principal researchers of the study, which was published in Cell Metabolism. Jiekun Yang, a researcher and scientist at MIT CSAIL; Maria Vamvini as medical instructor at Joslin Diabetes Center Joslin Diabetes Center, and Pasquale Ngro who is medical instructor of Joslin Diabetes Center. Joslin Diabetes Centerare principal authors of the research paper.

The dangers of obesity

Obesity is an increasing global health issue. Within the United States, more than 40% of the population is considered to be obese and more than 75 percent of them are overweight. Being overweight can be an indicator of risk for a variety of diseases, including cancer, heart disease as well as Alzheimer’s disease. even infectious diseases like Covid-19.

“Obesity together with ageing, is a major issue that affects all aspects of human health,” Kellis says.

A few years ago the lab of his was conducting an investigation about an investigation of FTO genes, which is heavily linked to the risk of obesity. In the study of 2015 the team of researchers found that genes located in this region regulate a process that triggers fat cells in the immature stage called progenitors adipocytes to transform into fat-burning or fat-storing cells.

This finding, which revealed that there is a distinct genetic factor to obesity, spurred Kellis to start looking into the ways that exercise, a widely-respected method of preventing obesity, may affect progenitors adipocytes on a cell level.

To investigate this issue, Kellis and his colleagues chose to conduct single-cell RNA sequencing on three types of tissues:muscles of skeletal, visceral white adipose tissues (found in the organs of the internal system which store fat) and Subcutaneous White Adipose Tissue (which is located under the skin and mostly burns fat).

The tissues were derived from mice belonging to four distinct experimental groups. For three weeks two mice groups received either a standard diet or a high-fat one. The following three weeks, the two groups was further separated into a sedentary group along with an exercise one that had access to treadmills.

In analyzing the tissues of these mice, researchers were able identify the genes affected or suppressed during exercise in 53 distinct cells.

Researchers discovered that in all three tissue types mesenchymal stem cell (MSCs) seemed to be able to manage some of the diet- and exercise-induced changes they observed. They are stem cells which have the ability to transform into different types of cells which include fat cells as well as fibrocytes. In adipose tissues, researchers discovered that a high-fat diet affected MSCs ability to develop into fat-storing cells and exercise reversed this process.

In addition to encouraging fat storage, the scientists discovered that a diet high in fat additionally stimulated MSCs to release factors that alter the extracellular matrix (ECM) -an array composed of protein and substances that protect and support tissues and cells within the body. This ECM restructuring helps create the structure needed for fat-storing cells that are larger and creates an inflammation-prone environment.

“As the adipocytes get filled with lipids, it creates an excessive quantity of stress. And this causes inflammation of a low grade, which is persistent and spreads for a long period of time,” Kellis says. “That is among the reasons that contribute to the many negative consequences of overweight.”

Circadian effects

The study also revealed that exercising and high-fat diets produced opposite effects on the cells that regulate circadian rhythms, those 24-hour rhythms that control numerous functions, ranging from sleeping to temperature of the body, release of hormones and digestion. The research revealed that exercising increases gene expression that regulate these rhythms however, a diet that is high in fat suppresses the production of these genes.

“There have been plenty of studies that have shown that the food you eat throughout the day is crucial in the way you absorb nutrients,” Kellis says. “The connection between circadian rhythm and food is one of the most important and demonstrates that the effects of exercise and obesity actually impact directly the circadian rhythm of peripheral organs that can affect distal clocks, and regulate stem cell functions and immune system.”

Researchers then examined their findings to a database of genes connected to metabolic characteristics. They discovered that two circadian rhythm genes identified in this study, referred to by the names DBP and CDKN1A as well as CDKN1A, have genetic variations that are associated with an increased risk of obesity among humans.

“These results will help us understand the potential translational value of these targets and how we can target particular biological processes in certain cells,” Yang says.

Researchers are currently analyzing samples of the small intestinal, liver, and brain tissues from mice involved in the study to study the effects of high-fat diets and exercise on the tissues. They also conduct research with human volunteers to collect biopsies, blood, and other samples to determine similarities and differences in the physiology of mice and humans. They hope their research will aid drug makers in the development of drugs that could duplicate some of the positive benefits of exercising.

“The general advice for all is to eat nutritiously and get active if you can,” Kellis says. “For those who find that this isn’t possible because of a lack of access to healthy food choices or because of limitations or other issues that hinder exercising, or simply the insufficient time to maintain an appropriate diet or healthy life style, what this study indicates is that we have a better understanding of the pathways, specific genes, and the particular cell and molecular processes should be controlled for therapeutic purposes.”

The research was supported with the help of the National Institutes of Health and the Novo Nordisk Research Center in Seattle.