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- A new study shows brain-derived estrogen can independently suppress appetite by making MC4R work better in the hypothalamus.
- Mice making estrogen just in the brain ate less and reacted better to leptin, making them feel full more strongly.
- Neuroestrogen may offer safer obesity treatments by keeping away from hormone effects across the body.
- Brain-derived estrogen affects memory, mood, and brain protection, which could matter for Alzheimer’s and thinking skills.
- Experts say studies in people are needed to check these results, even though early findings look promising for treatment.
Estrogen has been linked to reproduction for a long time, but new research shows a quieter, more complex job for a type of estrogen made right in the brain. This hormone, called brain-derived estrogen—or neuroestrogen—is made locally and is key in controlling appetite, metabolism, and thinking. As scientists look into this internal hormone system, a new story about estrogen is coming out. It could change how we handle obesity, brain cell problems, and behavior linked to the brain.
Estrogen Isn’t Just Made in the Ovaries
People usually see estrogen as something for reproduction, often tied to the ovaries in women. But over the last few decades, this narrow view has been questioned. Studies show estrogen is also made in other body parts, like fat, the adrenal glands, and most importantly, the brain.
The brain makes this estrogen using an enzyme called aromatase. Aromatase changes other hormones called androgens into estrogens. It works hard in certain brain areas, such as the hypothalamus, hippocampus, and amygdala. These brain areas control important things like how much we want to eat, how stable our mood is, how we form memories, and hormone balance. This shows neuroestrogen is very important, not just for reproduction.
Systemic estrogen goes all over the body through the blood. Neuroestrogen is different because it’s made and used right where it’s needed. This direct, nearby action means brain-derived estrogen can quickly and exactly affect nearby brain circuits. This makes it a very specific way the brain is controlled.
A Key Animal Study
A recent big study by researchers at Fujita Health University in Japan showed more clearly how powerful neuroestrogen is in the body. They made mouse models with special genes to see how brain-specific estrogen affected appetite and metabolism when the ovaries or other body systems weren’t making hormones.
The study used three kinds of mice
- OVX mice: Ovaries taken out by surgery, no systemic estrogen.
- ArKO mice: Genes were changed so they didn’t have the aromatase enzyme; they couldn’t make estrogen anywhere.
- BrTG-ArKO mice: Didn’t have systemic estrogen, but their genes were changed to let them make aromatase, and thus estrogen, only in the brain.
The results were surprising. Mice that could make estrogen only in their brain (BrTG-ArKO) ate much less than mice without estrogen. And then, these mice not only ate less, but they also showed more activity of genes that cut appetite in the hypothalamus.
Basically, even without estrogen from the ovaries or circulating in the body, brain-derived estrogen by itself was enough to control eating behavior. It worked like traditional estrogen treatments but without affecting the whole body.
How Neuroestrogen Affects Appetite Genes
One main way neuroestrogen controls appetite is through the melanocortin-4 receptor (MC4R). This gene is found in the hypothalamus and is very important for energy balance. We know it lessens appetite when it’s active.
In the study, BrTG-ArKO mice had more MC4R gene activity in parts of the hypothalamus. This acted like a strong internal signal to “slow down” hunger. Unlike hormones that travel through the blood, which might take time to get around and turn on genes that control appetite, neuroestrogen works locally. It increases gene activity almost right away.
Moreover, neuroestrogen also made more POMC (pro-opiomelanocortin) and managed NPY (neuropeptide Y). These are two other genes in the hypothalamus that have opposite jobs in controlling appetite
- POMC: Makes you feel full; more activity means you eat less.
- NPY: Makes you hungry; more activity means you eat more.
What’s notable is that neuroestrogen brings a balance between these genes. This helps the brain judge and react well to the body’s energy level.
Why the Hypothalamus Is So Important
People are seeing more and more that the hypothalamus is a control center. It doesn’t just handle appetite but also keeps the body in balance in wider ways, like controlling temperature, reacting to stress, and releasing hormones.
Inside this carefully managed brain area, neuroestrogen can work like a local helper. It helps make small adjustments about how much food to eat, how much energy to use, and how hormones give feedback. Since it’s made right in the area where these decisions happen, neuroestrogen works quickly and precisely.
This local effect is different from systemic estrogen treatments. Those treatments must travel through the whole body. This can take longer to get to the right spots. Worse, they might attach to places they shouldn’t, like cells in the breast or uterus, possibly raising the risk of cancer.
Can Better Leptin Response Help Fight Obesity?
One ongoing problem in dealing with obesity is not just eating too much, but leptin resistance. Leptin is a hormone from fat cells that tells the brain about stored energy and feeling full. Ideally, when there’s a lot of stored fat, leptin levels go up. This signals the brain to cut hunger.
But in many people who are overweight, the brain stops paying attention to leptin’s message. No matter how much leptin is in the blood, the brain ignores it. This is a state of resistance. The study from Fujita Health University found that mice with brain-made estrogen were more sensitive to leptin. Their hypothalamus neurons responded to lower levels of leptin, slowing down hunger signals more effectively.
These findings suggest that neuroestrogen might help fix the brain’s reaction to signals that usually make us feel full. If new treatments can safely increase neuroestrogen levels, they might help stop the cycle of overeating by fixing the body’s natural systems for controlling appetite.
Linking Neuroestrogen and Brain Health
Besides appetite and metabolism, estrogen has been seen for a long time as something that protects the brain. These protective effects include
- Actions against swelling that lessen brain damage from injury or sickness.
- Better synaptic plasticity, letting brain cells make and strengthen connections. This is key for learning and memory.
- More neurogenesis, especially in the hippocampus, a brain area needed for making new memories.
Much of this research used to focus on systemic estrogen. But new evidence suggests neuroestrogen alone can do these things that help the brain.
Actually, problems with estrogen signals in the brain have been tied to thinking skills getting worse early on, and to dementia. Women going through menopause—when systemic estrogen drops—often say they have “brain fog,” forget things, and have mood problems. People used to think these problems were only because of the drop in ovarian hormones. Now, scientists think they might also show a drop in neuroestrogen production inside the brain.
How Emotions and Appetite Could Be Tied to Hormones
Emotional eating, wanting certain foods when stressed, and comfort eating are often seen as behavior issues. But they are closely tied to chemical signals in the brain.
Brain areas like the amygdala and nucleus accumbens, which handle emotions and reward, also have aromatase and make neuroestrogen. This means how we feel emotionally and how much pleasure we get from food—like feeling satisfied or calmed—might actually be affected by the estrogen we make internally.
This hormone might change how much emotional importance we give to meals, snacks, or even cravings. If neuroestrogen levels drop, people might be more likely to eat because of stress or get hooked on sugar. But steady levels might help people eat in a measured and aware way.
Not All Estrogen Is the Same
Here is the really important point: estrogen throughout the body and estrogen made in the brain are not the same and cannot be swapped. The issue with standard hormone replacement therapies (HRT) is that they fill the whole body with estrogen. This can lead to unwanted results
- Higher chance of certain cancers (breast, endometrial)
- Increased possibility of blood clots or strokes
- Side effects such as sore breasts, mood shifts, or feeling sick
Brain-derived estrogen, on the other hand, only affects the cells in the brain where it’s made. If researchers can figure out how to specifically boost neuroestrogen—or copy how it acts in particular brain areas—we might be able to get great benefits without causing side effects elsewhere.
Changing How We Treat Things Based on Neuroestrogen
Because brain-made estrogen has special qualities, scientists are looking at new ways to treat problems. These ideas include
- Estrogen copies that target the brain and only attach to estrogen receptors in the central nervous system.
- Gene therapies or tools that change how genes work to increase aromatase in specific brain areas.
- Drug compounds that make the hypothalamus react better to existing hormones like leptin and insulin, with help from neuroestrogen.
- Ways of living or eating that help keep neuroestrogen levels up (for example, plant estrogens, exercise, reducing stress).
The chance to use these approaches for people struggling with messed-up appetite control, metabolic problems, or thinking skills getting worse is huge.
What’s Next in Neuroestrogen Research?
The team from Fujita Health University is looking into harder questions
- How does neuroestrogen guide emotional behavior and parts of the brain related to reward?
- How does making neuroestrogen change with age, stress, or harmful things in the environment?
- Could changing aromatase in a targeted way become custom medical treatments?
- How do differences between men and women affect what neuroestrogen does?
We expect high-tech imaging, gene editing, and better ways to watch the brain in real-time to speed up what we learn in the next few years.
Where There Are Still Limits
Even with all the excitement, most of the findings are from studies on mice. It’s not simple to apply them directly to human biology. There are differences in how long we live, brain size, how complex our brains are, and our hormone patterns. This means studies in people are necessary to prove these ideas. Also, how much neuroestrogen is made might be affected by things that are hard to predict, like sleep, what we eat, how much we move, and even how we interact with others. Each of these adds variability to what the research finds.
We also need to keep looking into safety. For instance: what happens if too much neuroestrogen is made? Could too much cause problems like eating too little, feeling worried, or mood problems?
What This Means for Health Around the World
The problem of too much obesity is still one of the biggest health issues everywhere. Standard ways of helping—like dieting, weight-loss medicines, and hormones for the whole body—often don’t deal with the brain processes that lead to eating too much.
Neuroestrogen offers an exciting new direction: a local influence run by the brain that controls appetite very precisely. By using this understanding, future treatments could work with our biology instead of against it. This could fix natural signals about hunger, metabolism, and reward.
Thinking Differently About Estrogen
As science finds out more about estrogen made in the brain, it’s clear we need to think about this hormone in a new way. Brain-derived estrogen is far from being just a sex hormone. It plays a vital part in clear thinking, managing emotions, and guiding appetite. It acts like a main controller inside the brain’s command centers, constantly adjusting how we behave and how we handle survival.
This change in how science sees things also makes it easier to have talks about hormones that feel better and include more people—especially men. Men also make neuroestrogen, though in smaller but still needed amounts.
Food, Mood, and Your Brain Hormones
You might think that wanting a snack late at night is just about how strong your will is. But it’s more likely your brain hormones working with incomplete information or mixed-up signals. As we learn more about neuroestrogen, we get new ways to deal with eating too much, mood problems, and even thinking skills getting worse early on.
Figuring out how the brain can make and use its own estrogen might be one of the most important health discoveries we make. And we are only just starting.
Citation
- Hayashi, T., Kumamoto, K., Kobayashi, T., Hou, X., Nagao, S., Harada, N., Honda, S., Shimono, Y., & Nishio, E. (2024). Estrogen synthesized in the central nervous system enhances MC4R expression and reduces food intake. The FEBS Journal. https://doi.org/10.1111/febs.17426
