New research uncovers a surprising role for brain-derived estrogen

A new study from Fujita Health University sheds light on how a brain-produced form of estrogen known as neuroestrogen plays a direct role in appetite regulation. The researchers found that neuroestrogen increases the activity of a key appetite-suppressing receptor in the brain and boosts the body’s response to the hunger-regulating hormone leptin. Their findings, published in The FEBS Journal, could pave the way for new treatments targeting overeating and obesity.

Estrogen has long been known to influence body weight and energy balance, but it was traditionally believed to act through the reproductive system. More recent findings, however, suggest that estrogen is also synthesized in the brain, particularly in areas such as the hypothalamus, through an enzyme called aromatase. This brain-derived version of estrogen—neuroestrogen—was suspected to influence behaviors and physiological processes beyond reproduction, but its specific function in appetite control had remained uncertain. The present study aimed to fill that gap.

To investigate the role of neuroestrogen, the researchers used several mouse models that differed in their ability to produce estrogen. One group included ovariectomized (OVX) mice, which had their ovaries removed and could no longer produce estrogen systemically. Another group consisted of ArKO mice, genetically modified to lack aromatase entirely and thus unable to synthesize estrogen anywhere in the body, including the brain. These groups were compared with normal mice and with a third group—BrTG-ArKO mice—engineered to restore aromatase expression specifically in the brain.

The team monitored the mice’s food intake and body weight over time and measured the activity of genes known to be involved in appetite regulation, including the melanocortin-4 receptor (MC4R), which suppresses appetite when activated. They also conducted experiments using hypothalamic neurons in cell cultures to test whether neuroestrogen directly affected MC4R gene expression.

Results showed that mice without systemic estrogen (OVX and ArKO mice) tended to gain more weight and consume more food than control mice. Interestingly, OVX mice initially showed a slight decrease in food intake after surgery but eventually gained more weight, suggesting complex hormonal feedback mechanisms. ArKO mice, which lacked both systemic and brain-derived estrogen, had lower levels of MC4R expression and a pronounced increase in food intake.

In contrast, BrTG-ArKO mice—engineered to produce neuroestrogen only in the brain—ate less and had significantly higher levels of MC4R in the hypothalamus than their ArKO counterparts. These mice also responded more strongly to leptin, the hormone secreted by fat cells that tells the brain when the body has had enough food. When administered leptin, BrTG-ArKO mice showed a greater reduction in food consumption compared to mice without neuroestrogen. This finding suggests that neuroestrogen boosts the brain’s sensitivity to appetite-suppressing signals.

Cell culture experiments reinforced the findings from the mouse models. When researchers introduced aromatase into hypothalamic neuron cells, these neurons began producing neuroestrogen and showed increased expression of the MC4R gene in response to testosterone or estradiol. The effect disappeared when aromatase activity was blocked, indicating that the rise in MC4R expression depended on estrogen synthesis within the neurons themselves. The experiments also confirmed that this effect was mediated through estrogen receptors, particularly ERα.

In addition to the effects on MC4R, the researchers found that neuroestrogen levels in the hypothalamus were correlated with other appetite-related genes, such as POMC and NPY. These genes help balance the signals that either suppress or promote food intake, suggesting that neuroestrogen acts at multiple points in the brain’s appetite-regulating system.

These findings offer a new understanding of how estrogen produced in the brain contributes to energy balance. While systemic estrogen from the ovaries can influence appetite, this study highlights that neuroestrogen has a more direct and localized effect by increasing the expression of key genes involved in suppressing hunger. It does so in part by enhancing the activity of MC4R and improving the effectiveness of leptin signaling.

However, the researchers caution that their work was conducted in mice, and more research is needed to determine whether similar mechanisms apply to humans. Hormonal regulation of appetite is highly complex and influenced by a wide range of factors including sex, age, and environmental conditions. Additionally, while this study focused on the hypothalamus, other brain regions involved in emotion and reward may also be affected by neuroestrogen and play roles in food-related behaviors.

Nevertheless, the results suggest that neuroestrogen could be a promising target for interventions aimed at appetite control. Obesity remains a growing global health issue, and many existing treatments have limited long-term success. A better understanding of how the brain itself regulates hunger through its own hormone production could lead to novel strategies for managing body weight.

The researchers plan to continue investigating how neuroestrogens influence other parts of the brain and how these hormones interact with stress and reward systems that also affect eating behavior. They hope their work can eventually contribute to the development of drugs that mimic or boost the effects of neuroestrogens in the brain without the side effects associated with systemic estrogen therapies.

The study, “Estrogen synthesized in the central nervous system enhances MC4R expression and reduces food intake,” was authored by Takanori Hayashi, Kanako Kumamoto, Tatsuya Kobayashi, Xinfeng Hou, Shizuko Nagao, Nobuhiro Harada, Shinichiro Honda, Yohei Shimono, and Eiji Nishio.