MIT and Harvard study unpacks the push and pull of diet and exercise

A new study from scientists at MIT and Harvard University has delved into the complex relationship between nutrition, exercise and the human body, and turned up some fascinating insights. The research explores the cellular mechanics of high-fat diets and physical activity, and how they can guide cells and bodily systems in healthy or unhealthy directions.

The new study stems from prior research carried out by MIT researcher Manolis Kellis that focused on the FTO gene region, which is associated with fat mass and obesity risk. This earlier work demonstrated how genes in this region regulate a signaling pathway that turns some types of immature fat cells into either fat-burning cells or fat-storing cells.

Since, Kellis has turned an eye to exercise to explore what kind of role it might play in this process. Together with colleagues at MIT and Harvard Medical School, Kellis performed single-cell RNA sequencing on skeletal muscle tissue, the white fat tissue packed around internal organs and the subcutaneous white fat tissue found beneath the skin.

These tissues were sourced from mice in four different experimental groups. Two groups of mice were fed either a normal diet or a high-fat diet for three weeks, and then those groups were further split into a sedentary group or an exercise group with access to a treadmill, for another three weeks. The tissues were then analyzed from the four groups, enabling the scientists to determine which genes were activated or suppressed by exercise in 53 different cell types.

“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.”

The analysis showed some interesting changes took place, with stem cells known as mesenchymal stem cells (MSCs) at the center of many of them. These cells can differentiate into other cells such fat cells or the fibroblasts that connect tissues and organs, and the scientists found a high-fat diet promoted their ability to differentiate into cells that store fat. Conversely, exercise was shown to reverse this effect.

Further, the high-fat diet caused the mesenchymal stem cells to secrete factors that altered the support structure around cells called the extracellular matrix. This reshaping of the matrix created a more inflammatory environment, and resulted in a new support structure more accommodating of fat-storing cells.

“As the adipocytes (fat cells) 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.”

Increasingly, we are seeing research that unravels the way our body clock, or circadian rhythm, can influence metabolism and the behavior of fat cells, and this new study also has relevance in this space. The authors found that high-fat diets suppressed the genes that govern circadian rhythms, while exercise had the opposite effect and boosted them. Two of these genes were matched with human genes linked to circadian rhythm and higher risk of obesity.

“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 said. “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.”

The scientists are now building on this work by analyzing samples of the mouse intestines, liver and brains to explore the changes on those tissues, and collecting blood and tissue samples from people to investigate the differences in human physiology. The authors consider the findings to be further evidence of how important a healthy diet and exercise are for our health.

But access to quality foods and being physically capable of regular exercise aren’t a given, and aren’t viable lifestyle interventions for everyone. For this reason, the scientists believe the findings are also important in that they point to new targets for drugs that might one day replicate the effects of exercise.

“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 Kellis.

The research was published in the journal Cell Metabolism.

Source: MIT

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