A photo of Stephanie Correa and Edward van Veen in Correa's UCLA laboratory

Research provides new insights into menopause and weight gain

A photo of Stephanie Correa and Edward van Veen in Correa's UCLA laboratory

Stephanie Correa and Edward van Veen in Correa’s UCLA laboratory (Photo Credit: Reed Hutchinson)

Can women in menopause get the benefits of hormone replacement therapy without the risks? A new UCLA study conducted with mice points in that direction, but additional research is necessary.

Women commonly experience hot flashes and weight gain, among other changes, during and after menopause. Hormone therapy, which gives women additional estrogen, can help alleviate some of these symptoms, but it has been linked to a higher risk of heart disease and breast cancer.

UCLA life scientists now report that a gene called reprimo, which is expressed by certain neurons in the brain, may play a role in menopause-related weight gain, a phenomenon not linked to increased eating. Their findings are published today in the journal Nature Metabolism.

“We want to figure out which neurons are mediating the beneficial portions of hormone therapy and mimic them without hormones,” said senior author Stephanie Correa, a UCLA assistant professor of integrative biology and physiology and a member of UCLA’s Brain Research Institute. “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.”

Correa and her research team show that the reprimo gene is important for regulating temperature. Changes in temperature are known to affect body weight and may contribute to the weight gain often seen in menopause.

“It’s possible that reprimo is involved in the weight gain that accompanies menopause,” said co-lead author Edward van Veen, a project scientist in Correa’s laboratory. “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 brain region called the hypothalamus is essential for survival in many species, from mice to humans; it controls eating, drinking, reproduction and body-temperature regulation, among other vital functions. Correa and her research team studied dozens of genes in the hypothalami of more than 50 mice, both female and male, starting at about eight weeks of age, shortly after they reach reproductive age.

The team used a technique known as single-cell RNA-seq, which allows biologists to study individual cells one at a time, to investigate which neurons in an area of the hypothalamus known as the ventromedial hypothalamus might mediate these different functions.

“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,” Correa said.

The biologists were most interested in neurons that have estrogen receptors. These receptors bind to the hormone and are subsequently able regulate to the activity of specific genes in the neuron, a process known as gene expression. The team’s most significant findings centered on the reprimo gene, which is expressed in one group, or population, of these estrogen-responsive neurons, restricted almost entirely 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 co-lead author Laura Kammel, a former UCLA doctoral student in Correa’s laboratory.

“The difference between females and males in reprimo in the ventromedial hypothalamus is like night and day,” Correa said. “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.”

In a series of experiments, the biologists interfered with the function of reprimo in the ventromedial hypothalamus in about two dozen mice. In one experiment, they shut off reprimo in female mice by using an RNA molecular compound that interferes with how the gene works in neurons. In another, they increased reprimo expression in male mice by removing an estrogen receptor from the neurons. In both cases, body temperature changed substantially, demonstrating a link between reprimo’s role in temperature and the effects of estrogen.

“We know that reprimo is important in regulating body temperature, but we don’t know what it is actually doing in neurons,” van Veen said. “We want to find out.”

Correa and her team also report that estrogen acts on another gene, Tac1, that is significantly increased in the ventromedial hypothalamus of female mice, although the difference is not nearly as dramatic as with reprimo. Tac1 has been shown to promote physical activity in female mice.

Estrogen receptor alpha, one of three estrogen receptors, is found in neurons in the same region of the ventromedial hypothalamus as Tac1 and reprimo. When the researchers removed that estrogen receptor, they found it led to obesity and reduced movement in female mice.

The results, the researchers said, not only aid in their understanding of the interplay between genes and estrogen but may also have implications for understanding obesity.

Summarizing the research, van Veen said: “The ventromedial hypothalamus is involved in movement and temperature regulation. We know estrogen affects movement and temperature. From Stephanie Correa’s previous research, we learned the estrogen response of neurons that affect movement, and now we think we know the estrogen response of neurons that affect temperature. It’s interesting that they are in the same location but distinct.”

“Our findings suggest reprimo is controlling some of the effects of estrogen on temperature,” Correa said. “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.”

Co-authors are co-lead author Laura Kammel, a former UCLA doctoral student in Correa’s laboratory; Xia Yang, a UCLA associate professor of integrative biology and physiology; Arthur Arnold, a UCLA distinguished professor of integrative biology and physiology; and Marc Liesa-Roig, a UCLA assistant professor-in-residence at the David Geffen School of Medicine at UCLA.

This article originally appeared in the UCLA Newsroom.

A photo of the sidewalk with chalk that says "Play your part, stay apart"

Play your part, stay apart: Advice and insight on physical distancing

A photo of the sidewalk with chalk that says "Play your part, stay apart"

Play your part, stay apart (Photo Credit: Jessica Wolf)

It has been a month since the wide-ranging safer-at-home directive went into effect in Los Angeles on March 17, following, and followed by, similar policies in other states and countries around the world.

It’s been hard. It’s wreaked havoc on our economy, our communities and our sense of emotional well-being. People understandably want to connect, go outside, share physical spaces, make a living, enjoy friends and family.

We asked Daniel Fessler, professor of anthropology and director of the UCLA Bedari Kindness Institute to help unpack why physical distancing feels so counterintuitive even while it represents one of the greatest mass acts of kindness — what scientists call “prosocial” behavior — we have witnessed as a species.

Why is it so hard to stay away from the people we are closest to socially? 

Our evolved mental mechanisms prioritize close social relationships over disease avoidance because those relationships were so important to the survival of our ancestors. One of the results of this is that we underestimate the risk of contagion that is posed by those to whom we are emotionally close. And as a consequence, people visit their relatives and close friends, and by so doing, they put at risk those whom they love the most.

The truth is, you’re probably even more dangerous to your loved ones than you are to strangers. After all, when’s the last time that you hugged a stranger on the street? If you care about the welfare of people you care about, then stay away from them.

Why is it so hard for us to fully accept that we might be dangerous to others, even if we don’t feel sick?  

Our evolved mental mechanisms are only attuned to overt cues of illness, so it’s difficult for us to grasp that we can be symptom-free and still infectious.

We can sort of understand that in an abstract way, but it’s hard for us to understand it in an emotional way. Likewise, our evolved mechanisms are attuned to harm that is tangible and immediate. The harm that we can do others is transmitted invisibly in this current situation and occurs after a delay of days or weeks. I’m quite confident that none of those college students who were partying on the beach in Florida during spring break would ever intentionally run over an elderly person in a crosswalk, but they’re potentially doing exactly that by contracting and spreading the virus.

How do we remind ourselves that staying away from one another physically is actually a huge act of kindness right now? 

As individuals, we all have a role to play in mitigating the impact of this disease. But problematically, social distancing doesn’t feel like prosocial behavior. And the reason it doesn’t feel like prosocial behavior is because in the world of our ancestors, helping other people and working together meant working face-to-face and side-by-side. You can think, for example, about how good it feels to help a stranger on the street or to work as a team to clean up trash on a beach or repaint an elementary school.

These things feel really good, right? And this is because our evolved psychological mechanisms are sensitive to cues that we are part of a prosocial cooperative group.

You may also think about how great it feels to do the wave with a huge crowd at a sporting event or to sing the national anthem together with thousands of people. These things are emotionally moving. They feel great because we are sensitive to the situation in which we’re coordinating our actions with those of many people around us towards a common goal.

Yet in the current crisis, for most of us, the first prosocial action that we must engage in is to stay away from other people. And ordinarily, staying away from other people can feel selfish. So staying away from other people doesn’t feel like we’re helping anyone.

I encourage everyone to think creatively. How can you help? For example, millions of kids are out of school right now. Can you tutor children via video link? Maybe just read a child a story. Many small businesses are in danger of going bankrupt. Can you purchase products or services at a distance that will help them to stay afloat?

Or maybe you can help deliver meals or medication to the elderly or to children who normally rely on school lunches and school nurses for their needs — of course, conducting yourself appropriately with regard to the safeguards of hygiene and social distancing when you are making those deliveries. Think outside the box. Get some ideas online. Find a way to help other people while still playing your part and staying apart.

What can we do to encourage others to continue to practice safe distancing until city and state leaders relax guidelines?

If you see someone ignoring social distancing guidelines, you need to acknowledge in discussion with them that you understand that it may seem safe because neither you nor they feel sick right now. But despite this, it doesn’t mean that either of you can’t transmit the virus to the other or to someone else. How we feel physically is simply not an accurate index of whether we might harm other people by being near them. Those kinds of conversations, of course, you need to hold at a safe distance, six feet or so.

In having those conversations, it’s helpful to think about language. Language can reflect the priorities and needs at the moment. People coin new words all the time. Just think, for example: Phrases like “gig economy,” “screen time” or “trending” weren’t things a few years back. I find acronyms particularly useful in this regard. You can Google the origins of two of my favorites — snafu (situation normal, all fouled up) and fubar (fouled up beyond all recognition) — two terms that were coined during other desperate emergency times.

We can coin a new acronym, a new word: PYPSA. It stands for “Play Your Part, Stay Apart.” You can use the word as praise for people who are doing a great job of social distancing: “Hey, man, way to go! You’re really PYPSA-ing,” and remind people who might forget or who might underestimate the importance of social distancing.

This article originally appeared in the UCLA Newsroom.