What scientists are learning about oestrogen and exercise

Oestrogen may change brain activity in ways that could impact how physically active we are, according to a remarkable new study in mice that looked at DNA, hormones and brain cells. Using advanced technology to pinpoint and reprogram specific genes and neurons in living animals, the study found that surges of oestrogen jump-started processes in the mouse brain that prompted the animals — even males — to become more active.

The study, published recently in Nature, involved mice. While humans share many of the same relevant hormones, genes and neurons, we are not mice and cannot yet say whether our brains and physiological systems work the same way. But the findings may open intriguing avenues of inquiry into why women so often become inactive after menopause, when oestrogen fades. The results also underscore how the brain and internal biological processes work together to play an unexpected and substantial role in whether the body gets up and moves or remains mostly still.

Increasing oestrogen levels in older women, might, in theory, encourage more movement, although oestrogen-replacement therapy remains a complicated subject.Credit:iStock

Moving and Mating

For nearly a century, since a famous 1924 study involving rats, scientists have known that female mammals tend to be most physically active just before they ovulate, when they are also most sexually receptive. This behaviour makes evolutionary sense, since female animals presumably need to be on the hunt then for a mate. In the intervening decades, researchers began to speculate that oestrogen must play a driving role in this behaviour, with subsequent studies indicating that female lab animals’ daily skitterings typically would surge and wane in tandem with their oestrogen levels.

But how could oestrogen, which primarily controls ovulation and other aspects of reproduction, influence physical activity? That physiological puzzle recently drew the attention of Holly Ingraham, a Herzstein Endowed Professor of Physiology at the University of California, San Francisco, who has a long-standing research interest in women’s physiology and metabolism. She and her collaborators wondered if oestrogen might somehow shape genetic activity in the brain, which would then activate brain cells in ways that could set in motion, well, motion itself.

To investigate that possibility, the scientists first gathered a crowd of healthy adult female mice and chemically blocked oestrogen uptake in some of them, while tracking how much all of the animals moved. Almost immediately, the animals without oestrogen became noticeably more sedentary than the other females, confirming that oestrogen somehow impacts physical activity.

Finding the Movement Cells

Next, the researchers examined the activity of a number of genes in the animals’ brains, noting that one, in particular, enthusiastically pumped out extra proteins when the animals’ brains were bathed in oestrogen but became almost quiet when oestrogen was absent. This gene, melanocortin-4, or Mc4r, previously had been linked in people to food intake and regulation of body weight. But the scientists now guessed it might also be the bridge between oestrogen and the impulse to be physically active, an idea they substantiated by using high-tech genetic mapping techniques refined by one of the study’s authors, Jessica Tollkuhn, an assistant professor at Cold Spring Harbor Laboratory School of Biological Sciences in Cold Spring Harbor, New York.

These techniques showed, in real time, oestrogen binding to Mc4r genes in certain neurons, especially those in a part of the mouse brain involved in energy expenditure. These brain cells also shared connections with other neurons elsewhere in the brain that control the speed at which animals move. Taken together, this experiment showed oestrogen firing up a particular gene that turns on certain brain cells that then should be expected to nudge an animal to move.

But the scientists had not yet seen these genes and neurons in action, so, as a final aspect of the study, they used a sophisticated technique known as chemogenetics to directly galvanise the relevant neurons in female mice that had been bred to produce no oestrogen. Once physically sluggish, these mice now explored, stood, played and ran far more than they had before.

Similarly, when the scientists used a form of the gene-editing technology CRISPR to gin up activity of the Mc4r gene in female animals’ brains, the mice became almost twice as active as before, a physical surge that persisted for weeks. Even male mice moved more when their Mc4r gene activity was dialled up by CRISPR, although not as much as the peripatetic females.

These results highlight the “complexity of physical activity behaviour,” Ingraham said, and how the willingness to spontaneously move — or not — for any animal probably involves an intricate interplay among genetics, endocrinology and neurology, along with conscious deliberation.

The study raises the intriguing possibility that the “timing of exercise, to have its most beneficial impact for women, might be fine-tuned by considering the changing hormonal milieu,” including the hormonal changes of menopause, said Dr. Tamas Horvath, a professor of neuroscience and obstetrics, gynaecology and reproductive sciences at the Yale School of Medicine and chair of the school’s department of comparative medicine.

“Of course, all these observations in mice need to be confirmed to operate in us, humans,” said Horvath, who was not involved in the current research. “However, the fact that this mechanism is found in an ancient part of the brain suggests that it will be applicable for most mammals, including humans.”

‘Knowledge is power’

Ingraham agreed. “We assume this circuit is working in humans, too,” she said, and, if so, the new study and any subsequent, related research could help to explain, in part, why inactivity is so common in women after menopause and also offer some potential strategies for overcoming the pull toward lassitude. Increasing oestrogen levels in older women, for instance, might, in theory, encourage more movement, although oestrogen-replacement therapy remains a complicated subject because of heightened cancer risks and other health concerns.

The study does hint, however, that it could, eventually, be possible to bypass oestrogen and re-create its effects with new therapies that would directly target the Mc4r gene or the relevant neurons in people’s brains and mimic the effects of oestrogen without the hormone itself. Any such medical advances are years in the future, Ingraham said.

Already, though, by delving into “the interrelationship between hormones and physical activity in females, this study has significant implications for human research studying the menstrual cycle and hormonal contraceptives and also menopause,” said Paul Ansdel, a lecturer in exercise physiology at Northumbria University in England, who was not involved with the study but has extensively studied menstruation and physical performance. “We know the importance of exercising in later life for promoting and maintaining health,” he said, “so the challenge for us now is to understand the best ways to stay active throughout the major hormonal transition that is menopause.”

This article originally appeared in The New York Times.

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