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Single-cell atlas reveals the genes behind exercise-induced weight loss

Written by Lauren Robertson, Science Writer.

A new study, published in Cell Metabolism, has revealed the cells, genes and pathways that are modified by exercise and high-fat diets. The resulting single-cell atlas provides an insight into the obesity or exercise-induced metabolic changes that occur in tissues and could offer new targets for therapeutic drugs that enhance or mimic the benefits of regular exercise.

A growing problem

In the US alone, more than 40% of the population is considered obese and 75% are classed as overweight. What’s more, the numbers are only growing – particularly in developed countries. Why does this matter? Because being overweight significantly increases your risk of developing serious diseases such as heart disease, cancer, infectious diseases like COVID-19, and Alzheimer’s.

Exercise is proven to be an effective measure to lose weight, but it is unclear exactly what cellular mechanisms are involved in the process. “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,” said co-author 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.

Back in 2015, Kellis and his team were looking into the effects of the FTO gene region that has been linked to obesity risk. They found that genes in this region control a pathway that prompts immature fat cells (progenitor adipocytes) to either become fat-burning or fat-storing cells. This demonstrated that there was a clear genetic component to obesity and prompted the team to look at how exercise could affect progenitor adipocytes at the cellular level.

Mesenchymal stem cells matter

They used mice as model for the experiments and put two different groups on either a high-fat or normal diet for three weeks. For the next three weeks, the two groups were divided again and either given access to a treadmill or made to be sedentary. They then used single-cell RNA sequencing to catalogue the responses of 53 different cell types found in the skeletal muscles and two types of fatty tissue – visceral white adipose tissue (found around internal organs) and subcutaneous white adipose tissue (found under the skin).

“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 said. “It says that exercise can really have a major effect throughout the body.”

Figure 1: Study overview, highlighted results, and phenotypic responses. (A) Overview of the mouse study and tissue profiling. (B) Summary of highlighted results. ECM, extracellular matrix. (C–F) Body weight (C), running distance (D), caloric intake (E), and glucose tolerance test (GTT) result (F) in the four intervention groups.

Importantly, the team discovered that mesenchymal stem cells (MSCs) – stem cells that can differentiate into cells like fat cells or fibroblasts – appeared to control many of the diet and exercise-induced effects. The high-fat diet seemed to modulate the MSCs’ ability to differentiate into fat-storing cells, and exercise appeared to reverse this effect.

Besides promoting fat storage, a high-fat diet also stimulated MSCs to secrete factors that remodel the extracellular matrix – a network of proteins and molecules that surround cells and tissues. The remodelling seemed to provide structure for enlarged fat-storing cells and created 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 said. “That is one of the factors that is contributing to many of the adverse effects of obesity.”

A sense of (circadian) rhythm

One unique finding from the study was that exercise boosts the expression of genes regulating circadian rhythms in the body – the 24-hour cycles that govern bodily functions such as sleep or digestion. On the other hand, a high-fat diet seems to suppress them.

When they compared their results with a database of genes linked to metabolic traits, they found two circadian rhythm genes they identified in their study had already been linked to a higher risk of obesity in humans.

“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.”

As for next steps, the team are now analysing samples of small intestine, liver, and brain tissue from mice to explore any effects of exercise in these areas. They are also attempting to translate their findings into humans by studying blood and biopsies from volunteers.

Overall, the age-old advice remains the same: eat well and exercise regularly. But for those people who are unable to do this (for example those with low access to healthy foods or due to disabilities preventing exercise), there could be other solutions on the horizon. “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,” said Kellis. The team hopes their findings will help guide drug developers to design drugs that might mimic some of the beneficial effects of exercise.