RELMalpha Protein Provides Females with Obesity Protection, Scientists Reveal

Research conducted using a mouse model to explore sex disparities in obesity has led to an interesting discovery by scientists. They uncovered that female mice, in contrast to males, exhibit greater resistance to obesity and inflammation. This is due to an increased secretion of an immune protein known as RELMalpha. The findings highlight a significant ‘RELMalpha–eosinophil–macrophage axis’ present in females, suggesting potential innovative therapies to tackle obesity.

This mouse study by UC Riverside sheds light on the mechanisms underlying sex differences in obesity.

The team at UC Riverside observed that the immune protein RELMalpha aids female mice in resisting obesity. However, when this protein was removed, the females showed susceptibility to obesity similar to their male counterparts. This underscores the potential for new obesity treatments and emphasizes the need to consider sex differences when addressing metabolic diseases.

With detrimental health outcomes and diminished quality of life, obesity has become a growing concern in the United States, affecting over 30% of American adults. Obesity, being a risk factor for multiple diseases including diabetes, cardiovascular disease, and COVID-19, is indeed a crucial and escalating public health issue.

RELMalpha: An Obesity-Combatting Protein

In a high-fat diet-induced obesity mouse model, scientists from the University of California, Riverside, determined that female mice, compared to males, are shielded from obesity and inflammation due to an increased secretion of the immune protein RELMalpha.

Meera Nair, an associate professor of biomedical sciences at the School of Medicine, co-led this study published in eLife along with Djurdjica Coss, a professor of biomedical sciences. Nair explains, “Our study identifies immune cells and RELMalpha as factors contributing to these sex-specific differences in the immune response to obesity.”

Understanding the Function of RELMalpha

Resistin-like molecules, or RELM, compose a protein family secreted by mammals, which is highly active in infectious and inflammatory diseases. One such protein, RELMalpha, protects the body’s tissues and is quickly triggered following an infection. Its sequence and function are similar to resistin in humans.

Nair explained the role of RELMalpha in regulating two immune cell types: the anti-inflammatory macrophage and the eosinophil. She adds, “In contrast, males expressed less RELMalpha, had less eosinophils, and had inflammatory macrophages that promoted obesity.”

Study Outcomes and Potential Impact

The researchers found that, upon deleting RELMalpha in female mice, they were no longer safeguarded from obesity. They had fewer eosinophils and had inflammatory macrophages — resembling the situation in male mice. However, obesity in these female mice could be reduced by treating them with eosinophils or with RELMalpha, suggesting promising therapeutic targets.

According to Djurdjica Coss, “The implications of our study are that consideration of sex differences is critical to tackle metabolic diseases such as obesity.”

The researchers discovered that RELMalpha deficiency had significant impacts on males as well, although the effects were less pronounced than in females. This is likely because female mice had higher levels of RELMalpha than males.

Conclusion and Future Therapies

This study illuminates a previously unacknowledged role for RELMalpha in moderating metabolic and inflammatory responses to diet-induced obesity that is sex-dependent, Nair explains. She further adds that their findings accentuate a crucial ‘RELMalpha–eosinophil–macrophage axis’ in females, providing protection from diet-induced obesity and inflammation. Therefore, enhancing these pathways could provide innovative therapies for combating obesity.

Nair and Coss were accompanied in the study by Jiang Li, Rebecca E Ruggiero-Ruff, Yuxin He, Xinru Qiu, Nancy Lainez, Pedro Villa, and Adam Godzik of UCR. The study received support from grants to Nair and Coss from the National Institutes of Health.

The research paper is titled “Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils,” and it has been published in the journal eLife.

Reference: “Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils” by Jiang Li, Rebecca E Ruggiero-Ruff, Yuxin He, Xinru Qiu, Nancy Lainez, Pedro Villa, Adam Godzik, Djurdjica Coss and Meera G Nair, 10 May 2023, eLife. DOI: 10.7554/eLife.86001

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More about RELMalpha in Obesity Resistance

• [UC Riverside]
• [The Journal eLife]
• [National Institutes of Health]
• [Study on RELM Proteins]