A new study published in the journal Nature Metabolism in April 2020 indicates that some genes could allow women in menopause to remain healthy without hormone replacement therapy, which has been linked to a higher risk of heart disease and breast cancer.
Menopause symptoms
Women all over the world tend to perceive menopause as a painful phase of life, with hot flashes and weight gain being just two of the many uncomfortable symptoms. Traditionally, these symptoms are treated with hormone replacement therapy, which provides additional estrogen to women as their natural estrogen depletes. However, estrogen therapy is not without its own dark side, as it has been linked to cancer and heart disease in clinical trials.
A new UCLA study on mice has begun to explore the possibility of bypassing hormone therapy by identifying a gene that may be responsible for menopausal weight gain.
Senior author Stephanie Correa, an assistant professor of integrative biology and physiology at UCLA, explains, "We want to figure out which neurons are mediating the beneficial portions of hormone therapy and mimic them without hormones."
The aim of the team is to trace the benefits of estrogen therapy to the neurons which are responsible for them and identify a therapy that targets those particular neurons, thus reducing its unintended side effects on the rest of the body.
Stephanie Correa and Edward van Veen in Correa's UCLA laboratory. Image Credit: Reed Hutchinson/UCLA
Tracing genes to bypass hormones
The research team has found that the gene, reprimo, which is expressed in particular neurons in the mouse brain, is linked to temperature regulation in the body. Changes in temperature do influence body weight and, as such, maybe a contributory factor to menopausal weight gain. The researchers, therefore, want to establish the presence of reprimo neurons in the hypothalamus in humans as well and to learn how they can be modulated.
The work centered on the ventromedial hypothalamus. The hypothalamus is the part of the brain that is thought to influence satiety, sexual and physical activity, temperature regulation, and obesity. It is necessary for survival in many species.
The scientists examined the function of dozens of genes in more than half a hundred mice from about eight weeks of age, which is when they become sexually mature. They used single-cell RNA-seq to analyze cells individually. This lets them identify the different types of nerve cells in this area and how different functions were related to each of these cells. They also looked at the differences in cell function between male and female mice because it is already established that the ventromedial hypothalamus acts very differently in the two sexes.
The study further narrowed its focus to neurons with estrogen receptors - molecules that bind to estrogen and subsequently regulate gene expression. Significantly, females were found to have almost all of the type of estrogen-responsive neuron which expresses reprimo. Correa compared the difference in expression of reprimo in males and females to "night and day", and stated that it was "easily the strongest sex difference that I have ever seen" of all her gene studies in the ventromedial hypothalamus.
Next, they had to identify the role of reprimo. "We know that reprimo is important in regulating body temperature, but we don't know what it is actually doing in neurons," said project scientist and co-lead author Edward van Veen.
The research team investigated the role of reprimo by inhibiting its function in mice. Reprimo functioning was stopped in female mice using an RNA molecular compound that suppressed the functioning of the gene (simulating the role of estrogen). They increased its functioning in male mice by removing one type of estrogen receptor from the nerve cell. Results showed changes in body temperature following such gene-level interventions, indicating a link between reprimo-caused temperature regulation and the effect of estrogen.
Says researcher Edward van Veen," "It's possible that reprimo is involved in the weight gain that accompanies menopause." If the findings are replicated in humans and if such neurons can be manipulated, it could help avoid hormone therapy while mitigating weight gain.
The team also discovered the role of another gene, Tac1, that is present at higher levels in this area in female mice, though the difference between the sexes is less pronounced in this case. Tac1 plays a role in regulating physical activity in female mice. Tac1 and reprimo shared one common link - they were both found in higher numbers in females.
Researchers also found that removing estrogen receptor alpha - found on neurons in the same region of the ventromedial hypothalamus as Tac1 and reprimo - led to obesity and decreased movement in female mice.
All these results help understand how genes and estrogen affect each other and also influence the development of obesity. One, the ventromedial hypothalamus regulates movement and temperature. Two, estrogen also affects these parameters.
Earlier research by Correa establishes how neurons that affect movement respond to estrogen. The current study shows how neurons involved in temperature regulation respond to this hormone. And, says Correa, "It's interesting that they are in the same location but distinct." This could mean that estrogen's effects on temperature regulation are partly modulated by reprimo.
Correa concluded by stating that, if indeed estrogen-responsive reprimo was partly responsible for menopausal weight gain by its effects on body temperature, then it could possibly be manipulated to give patients an alternative to estrogen therapy that avoids the side effects. Further research is necessary to cement the role of reprimo, and to identify therapies that target it effectively.
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