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Experts identify a gene that may regulate menopause symptoms

Experts identify a gene that may regulate menopause symptoms. Experts at UCLA have identified a gene that may play a central role in menopause-related hot flashes and weight gain. The gene, called reprimo, is expressed by certain neurons in the brain.

It is common for women to experience weight gain during menopause that is not directly related to food, as well as other symptoms like hot flashes. While hormone therapy may be effective, it is linked to a higher risk of heart disease and breast cancer.

The discovery of a gene that can be targeted opens up the possibility of safer treatments to curb weight gain and other menopausal changes. 

Study senior author Stephanie Correa is an assistant professor of Integrative Biology and Physiology at UCLA and a member of the Brain Research Institute.

“We want to figure out which neurons are mediating the beneficial portions of hormone therapy and mimic them without hormones,” said Professor Correa. “Hormone therapy can be beneficial, but it treats the entire brain and body with hormones. We may be able to bypass the hormone. That’s our goal, and it’s a big one. We haven’t achieved it yet, but we’re learning.”

The researchers determined that the reprimo gene plays an important role in temperature regulation. Changes in temperature, which are known to affect body weight, may promote menopause-related weight gain.

“It’s possible that reprimo is involved in the weight gain that accompanies menopause,” explained study co-lead author Edward van Veen. “If equivalent neurons exist in humans and we can find some way to tweak them, it might relieve much of the weight gain without the side effects of hormone therapy.”

A technique known as single-cell RNA-seq allows biologists to study individual cells one at a time. The researchers used this technique to analyze dozens of genes in the hypothalamus brain region of mice.

In both humans and mice, the hypothalamus controls many functions that are critical for survival, such as eating, drinking, reproduction, and body-temperature regulation.

“We had hints there were different types of neurons in the ventromedial hypothalamus, and this region is very different in males and females, so we studied hundreds of cells in males and females to identify the different types of neurons and determine whether there are sex differences,”said Professor Correa.

The experts paid close attention to neurons that have estrogen receptors, which can bind to the hormone and control gene expression. The study revealed that the reprimo gene, which is expressed in one group of neurons with estrogen receptors, was almost entirely restricted to females.

“We were excited to find not only populations of estrogen-responsive neurons but also differences in these populations between males and females,” said study co-lead author Laura Kammel.

“The difference between females and males in reprimo in the ventromedial hypothalamus is like night and day,” said Professor Correa. “The females express a ton of it, and males express little, if any, reprimo in this brain region. Of the dozens of genes I have studied in this region, this is easily the strongest sex difference I have ever seen.”

The researchers interfered with the function of reprimo in about two dozen mice. They shut off reprimo in female mice by using an RNA molecular compound. In a separate trial, reprimo expression was increased among male mice. Both experiments resulted in dramatic changes in body temperature, which confirms a link between the effects of estrogen and the role of reprimo in body temperature. 

“Our findings suggest reprimo is controlling some of the effects of estrogen on temperature,” said Professor Correa. “If it is controlling the beneficial effects, then maybe we can manipulate it – with a drug that targets reprimo or the neurons that express reprimo – as an alternative to hormone therapy and get around the requirement for estrogen. We are studying the brain in a nuanced way and trying to learn which cells or which genes are important to target for potential therapies.”

The study is published in the journal Nature Metabolism.

By Chrissy Sexton, Staff Writer


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