Researchers Suggest Explanation for Postmenopausal Weight Gain

A new study has found that a reduction in estrogen receptors in the heart results in obesity in female mice, but not male mice – findings that may provide important health insights for postmenopausal women. The research is published in Nature Cardiovascular Research.

Estrogen and the heart

The sex hormone estrogen has many important roles in the body – one of which is protecting women’s heart tissue. However, once women reach menopause and estrogen levels decline, this protection is diminished, and the risk of developing several conditions such as heart disease, obesity and diabetes rises significantly.

To explore the protective effects of estrogen on the heart, the researchers investigated the role of its receptor, estrogen receptor alpha (ERα), on cardiomyocytes. These are the heart cells that allow the heart to contract and pump blood around the body.

“We’ve been interested in trying to understand the role of this estrogen receptor in the heart for some time, to see how it provides protection to the heart,” said Professor Julie McMullen, co-senior author of the study.

Effects on obesity

From experimental mouse studies, McMullen and colleagues found that reduced levels of ERα led to obesity and mild heart dysfunction in female mice, but not in male mice.

“When we blocked this estrogen receptor, we were expecting to see changes and damage largely to the heart,” McMullen explained. “But rather than seeing a dramatic heart phenotype, what we saw was an adiposity phenotype. So, we observed that the female mice were heavier and had more fat mass, which we weren’t expecting at all.”

Furthermore, genetic analysis revealed the possible cause for the mild heart dysfunction, i.e., why their hearts did not pump as well. The findings showed that in the female mice, reduced ERα levels lowered expression of genes that are important for the heart’s contraction and healthy metabolism.

Reduced ERα in the hearts of female mice also led to changes in extracellular vesicles – lipid particles that are released from cells containing cargo such as proteins and nucleic acids. The researchers found that extracellular vesicles released from female hearts contained different proteins to those from the control groups and males.

“We found that reducing ERα in heart muscle cells of female mice leads to transcriptional, lipidomic and metabolic dysregulation in the heart, together with metabolic dysregulation in skeletal muscle and adipose tissue,” said Associate Professor David Greening, co-senior author of the study and expert in extracellular vesicles.

“Furthermore, the extracellular vesicles that are released from heart cells with reduced ERα had the capacity to reprogram skeletal muscle cells in cell culture. These changes to tissues, the extracellular vesicles’ proteome and reprogrammed skeletal muscle cells altered the cells’ molecular landscape and function. So rather than energy being expended, energy is instead stored, which explains the increased adiposity in female mice in the absence of ERα,” Greening added.

Therapeutic implications

Overall, the findings of the study may provide important insights for the prevention or treatment of heart and metabolic diseases among postmenopausal women. Additionally, the study could have important implications for reducing toxicity to the heart caused by therapies that can adversely affect ERα.

“Females who have drugs that can interact with or inhibit this particular receptor, including some chemotherapies, often become obese,” McMullen elaborated. “Now we have a better understanding of ERα, we've got a better chance of identifying therapies to prevent the obesity from occurring.”

Greening also highlighted the study’s implications on our understanding of extracellular vesicles, suggesting that they are “systemic signaling regulators that can travel to, and impact other organs in the body, including adipose tissue and skeletal muscle.”

Reference: Tham YK, Bernardo BC, Claridge B, et al. Estrogen receptor alpha deficiency in cardiomyocytes reprograms the heart-derived extracellular vesicle proteome and induces obesity in female mice. Nat Cardiovasc Res. 2023:1-22. doi:10.1038/s44161-023-00223-z

This article is a rework of a press release issued by La Trobe University. Material has been edited for length and content.