Beyond regulating reproduction, estrogen plays an essential role in metabolic control. The decline in this hormone’s levels during postmenopause promotes visceral fat accumulation, disrupts glucose and lipid homeostasis, and increases the risk of metabolic diseases. Hormone replacement therapy with estradiol can mitigate some of these effects, but it is not indicated for women with a predisposition toward hormone-dependent tumors.

Now, a study conducted by researchers from RIDC Redoxoma has shown that selective activation of estrogen receptor beta, one of the receptors that mediates the cellular actions of the hormone, improves lipid and glucose homeostasis and promotes metabolic reprogramming in the liver. The finding points to a promising strategy to combat postmenopausal metabolic changes without activating the pathways associated with the proliferative effects of estrogen.

“What I find interesting about this work is that we focused on the beta-type estrogen receptor, which was still poorly investigated for its role in metabolism, and we managed to show that it is a potential target for research,” said Débora Santos Rocha, lead author of the study, published in the journal Comprehensive Physiology. The work was developed during her postdoctoral research at the Laboratory of Energy Metabolism at the Instituto de Química of USP, under the supervision of Professor Alicia Kowaltowski.

Estrogen receptors

In cells, estrogen acts through three main types of receptors: the nuclear estrogen receptors alpha (ERα) and beta (ERβ), which regulate gene expression, and membrane receptors, which mediate rapid responses to the hormone. Estradiol used in hormone replacement therapy activates all of them.

For many years, most research has focused on receptor alpha, which is responsible for most of the classic effects of estrogen. In previous studies, its activation has been associated with improved energy metabolism, increased insulin sensitivity, and reduced fat accumulation in the liver. On the other hand, it is also related to the proliferative effects of the hormone in tissues such as the breast, uterus, and ovaries, which may favor the development of hormone-dependent tumors.

Estrogen receptor beta, discovered only in the 1990s by the group of Swedish researcher Jan-Åke Gustafsson, is also present in several tissues, and previous studies had already suggested that its activation could improve insulin sensitivity and reduce lipid accumulation, in addition to exerting antitumor effects, such as inhibiting cell proliferation and the formation of new blood vessels. However, the mechanisms responsible for the metabolic benefits were still poorly understood, as was its role in postmenopausal conditions.

To address these questions, Rocha explains, the researchers evaluated the effects of selective ERβ activation in experimental models of estrogen deficiency. To do so, they used diarylpropionitrile (DPN), a selective receptor agonist. In rats subjected to ovariectomy, a procedure that mimics the condition observed during postmenopause, the compound was administered to evaluate its impact on metabolism. In parallel, liver cells were exposed to nutrient overload to investigate the cellular mechanisms involved in the effects observed in the animals.

In the animals, receptor activation restored fasting glucose levels and the lipid profile, improved pancreatic islet morphology, and reduced retroperitoneal white adipose tissue. It also restored circulating concentrations of free fatty acids and ketone bodies to the levels observed in control animals, indicating a reorganization of hepatic lipid metabolism. In addition, it promoted extensive remodeling of the liver lipidome, an effect the researchers characterized in detail through lipidomic analysis.

“What we saw in the in vivo model, to our surprise, was a reversal of the circulating lipid profile,” Rocha highlighted. According to the researcher, the castrated animals showed increased triglycerides, cholesterol, and free fatty acids, “everything that’s bad for lipid metabolism.” With treatment, these changes were reversed.

The detailed analysis of the liver lipidome, performed in collaboration with Sayuri Miyamoto’s group, showed that ERβ activation does not simply alter the amount of fat present in the liver, but rather modifies its composition.

“When we evaluated the lipidome, that is, the different lipid species, we saw that the treatment promotes remodeling in these ovariectomized animals. The total amount of fat in the liver does not change, but the lipid profile changes. It is as if the treatment favored a more protective profile, because the cell can store fat, but depending on the type of lipid that accumulates, this storage can become toxic.“

To understand how this remodeling occurs, the team reproduced in hepatic cell culture the nutrient overload conditions observed during estrogen deficiency. Treatment with DPN reduced ketone body production to the levels observed in control cells and favored the complete oxidation of fatty acids in the mitochondria.

According to Kowaltowski, this mechanism may explain the metabolic effects observed in the treated animals

“The liver generally uses fatty acids as an energy source, but doesn’t oxidize them completely. It produces ketone bodies, which it releases into the bloodstream to serve as an energy source for other organs. But what this study shows is that, when this beta receptor is activated, the liver begins to oxidize these fatty acids more completely. And perhaps that’s precisely why all this remodeling occurs, along with a smaller accumulation of lipids that are harmful to the liver.“

The results obtained so far reinforce the potential of selective activation of the estrogen receptor beta as a strategy for the development of new treatments against metabolic changes associated with post-menopause, especially for women who cannot undergo hormone replacement therapy.

Women’s health

Although hormone replacement therapy is effective for many patients, it is not indicated in all clinical situations.

“The goal of this study is precisely to present a potential alternative to hormone replacement therapy. Starting hormone replacement therapy after the age of 65 is not recommended, which leaves this population unassisted. There is also another group of women, at risk of developing breast cancer or other gynecological cancers, or who have already undergone treatment for this type of cancer, that cannot receive hormone replacement therapy. So there is a significant portion of the population that goes unassisted during this stage of life. Postmenopause lasts for a long time, considering women’s life expectancy,” emphasizes Rocha.

According to Kowaltowski, the dyslipidemia observed after menopause is associated with an increased risk of cardiovascular diseases, stroke, type 2 diabetes, and neurodegenerative diseases. “Controlling lipid levels is very important, it has enormous therapeutic potential.“

Kowaltowski points out that interest in women’s health research has been growing. One example of this trend is that, upon submitting the article to a journal of the American Physiological Society, the researchers found that it fit within a special ongoing call for papers dedicated to the topic.

Next steps

In a new phase of the research, supported by a FAPESP Geração Project, Rocha intends to further her studies using an experimental model that more accurately reproduces the transition to menopause.

“Now, in my group, I will study a menopause model that is a bit different from ovariectomy. Because, as we can imagine, castrating an animal does not fully mimic menopause, which is a progressive process. So we will develop a follicular depletion model.” Unlike surgical removal of the ovaries, this model promotes a gradual reduction of the ovarian reserve.

“With the progressive decline in estradiol and the onset of these changes, we create a window of possible therapeutic intervention. So, at this first stage, we’re going to characterize this model at the macroscopic and molecular levels, in order to identify therapeutic targets both during and after menopause.“

The article “Estrogen Receptor Beta Activation Coordinates Liver Lipid Remodeling and Metabolic Fluxes, Preventing Lipotoxicity”, by Débora Santos Rocha, Eloisa Vilas-Boas, Camille C. Caldeira da Silva, Everton L. Vogt, Marcos Yoshinaga, Mariana Pacheco Teixeira de Carvalho, Maiara I. C. Queiroz, Tiago Eugênio Oliveira da Silva, Sayuri Miyamoto, and Alicia J. Kowaltowski, is available at this link.