Exercise is widely known for helping people shed weight and keep it off. 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 that broadens researchers’ knowledge of how diet and exercise influence your body MIT as well as Harvard Medical School researchers have identified several of the cells that, genes, and cellular pathways affected by high-fat diet. These findings could provide avenues for pharmaceuticals that can aid in enhancing or replicating what benefits exercise can bring the researchers claim.

“It is crucial to know the molecular processes that drive the positive effects of exercise, as well as the negative consequences of a diet high in fat to be able to modify our approach and create drugs that mimic the effect 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 researchers examined mice that had regular or high-fat diets that were either sedentary or had the option to exercise at any time they desired. By using single-cell RNA sequencing researchers recorded the response of 53 different kinds of cells that are found in the skeletal muscle as well as two kinds of fatty tissue.

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

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 lead authors 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 Nicolo as medical instructor in Joslin Diabetes Center. Joslin Diabetes Centerare principal authors of the research paper.

The risk of obesity

Obesity is an increasing global health issue. Within the United States, more than 40 percent of the populace is considered overweight and more than 75 percent are overweight. Being overweight can be an indicator of risk for many illnesses, such as cancer, heart disease Alzheimer’s disease, cancer, and some infectious diseases, like Covid-19.

“Obesity together with ageing, is a major factor that impacts the health of everyone,” Kellis says.

In the past his lab conducted research of his lab’s study of the FTO genes, which is heavily linked to the risk of obesity. In the study of 2015 the team of researchers found that the genes within this region regulate a process that triggers fat cells in the immature stage known as progenitor adipocytes, to transform into fat-burning or fat-storing cells.

The study, which showed that there is a distinct genetic factor to obesity, prompted Kellis to start looking into the ways that exercise, a widely-known method of preventing weight gain, could affect progenitors of adipocytes at a cells level.

To investigate this issue, Kellis and his colleagues have decided to do single-cell RNA sequences of three types of tissuemuscles of skeletal, visceral white adipose tissues (found within internal organs which store fat) and the subcutaneous white tissue adipose (which is found beneath the skin and mostly burns fat).

The tissue was derived from mice in four different experimental groups. For three weeks two mice groups had been fed with either a regular diet or a high-fat one. The following three weeks, the two groups was further divided into a sedentary along with an exercise one with access to treadmills.

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

Researchers discovered that across all three types of tissue mesenchymal stem cell (MSCs) were able to regulate some of the diet- and exercise-related effects that they observed. They are stem cells which are able to differentiate into various cell types such as fat cells and fibrocytes. In the adipose tissue of the body, researchers found that a high fat diet altered MSCs ability to transform into fat-storing cells and exercise reversed this process.

Alongside promoting fat storage, the scientists discovered that a high-fat diet additionally stimulated MSCs to secrete substances which remodel the extracellular matrix (ECM) -an array of proteins as well as other molecules that support and surround tissues and cells within the body. This ECM restructuring helps create structure to the fat-storing cells and creates an inflamed environment.

“As the adipocytes get saturated with lipids, they’ll experience an excessive degree of stress and this causes inflammation of a low grade, which is systemic , and can be sustained for a long period of time,” Kellis says. “That is among the reasons that contribute to the many negative consequences of weight gain.”

Circadian effects

The study also revealed that exercising and high-fat diets have opposite effects on the cell pathways that regulate the circadian rhythms, which are these 24-hour cycle cycles control various functions, from sleeping and body temperatures, to hormone production and digestion. The study found that exercise enhances transcription of the genes which regulate these rhythms however, a diet that is high in fat suppresses these rhythms.

“There are a number of research studies that show that what you eat throughout the day is crucial in how you absorb energy,” Kellis says. “The connection between circadian rhythm and food is one of the most important and demonstrates that fitness and obesity can directly affect the rhythm of the circadian cycle in peripheral organs. These organs can affect distal clocks, and regulate stem cell functions and immune system.”

Researchers then examined their findings to a database of genes that have been associated to metabolic traits. They discovered that two circadian rhythm genes that they discovered in the study, identified by the names DBP and CDKN1A and CDKN1A, are genetically mutated that are associated with the risk of being overweight among humans.

“These results will help us understand the translational potential of these targets, as well as the possibility of targeting particular biological processes in certain cells,” Yang says.

The researchers are currently studying small intestine samples as well as liver and brain tissues from mice involved in the study to study the effects of diets high in fat 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 mouse and human. They hope their research will aid drug makers in the development of drugs that could replicate some of the beneficial benefits of exercising.

“The advice for everyone should beto consume 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 nutritious foods or because of physical disabilities, or other reasons which hinder exercise, or simply the lack of 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, as well as the specific biological and cellular processes we can manipulate for therapeutic purposes.”

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