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What Gives Exercise Its Beneficial Effects

Researchers working with mice have identified molecular links between exercise and some of its beneficial effects. Exercise does more than make muscles stronger: it comes with a host of metabolic and psychological benefits. Understanding the mechanisms through which exercise improves health might help us to get more from exercise, or even to obtain some of its health benefits in other ways, without working out. In a new study, scientists considered the possibility that exercise might induce cells in some parts of the body to secrete more or less of various proteins that play a key role in regulating metabolic health. Secreting such proteins into the bloodstream can enable signaling between cells in different parts of the body to affect health.

Accordingly, they developed a method to track changes in protein secretion from 21 different cell types in mice and found that exercise caused changes in the cells’ secretion of numerous proteins into the blood. Among these was a significant increase in the secretion by liver cells of CES2A and CES2C, two closely related proteins called carboxylesterases. To determine whether secreted CES2 proteins play an important role in mediating the effects of exercise, they developed strains of mice with liver cells that secrete CES2A or CES2C whether or not the mice exercise. Both forms of CES2 protein partially protected these mice from the effects of an unhealthy diet that causes weight gain and would otherwise have resulted in type 2 diabetes. The mice that secreted more CES2 from their liver cells gained less weight, and they did not develop signs of diabetes but instead had relatively normal glucose (sugar) levels and remained more responsive to insulin. Secretion of the proteins did not affect weight gain or insulin sensitivity in mice fed a healthier diet, but those secreting CES2C were able to run faster and exercise longer without prior training than mice secreting CES2A or an unrelated control protein. These findings suggest that both CES2 proteins have a role in helping produce some of the beneficial metabolic effects of exercise in mice, and that CES2C might have a role in helping the mice improve exercise performance and endurance.

If carboxylesterases turn out to have a similar impact on metabolism in humans, or if other proteins secreted in response to exercise also influence metabolism, this research could one day lead to approaches that help people get the most metabolic benefit they can from whatever amount of exercise they do.

Wei W, Riley NM, Lyu X,…Long JZ. Organism-wide, cell-type-specific secretome mapping of exercise training in mice. Cell Metab 35: 1261- 1279.e11, 2023
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