Obesity is on the rise in the US, linked to negative health outcomes and a lower quality of life. Over 30% of American individuals are currently considered clinically obese. Obesity is a significant and expanding public health issue as it is a risk factor for several diseases, including diabetes, cardiovascular disease, and COVID-19.
Researchers from the University of California, Riverside discovered that female mice are more resistant to obesity and inflammation than male mice because they release more of an immune protein called RELMalpha. This immune protein is believed to defend against inflammation and obesity.
Our study identifies immune cells and RELMalpha in causing these sex-specific differences in the immune response to obesity.
Meera G. Nair, Study Co-Lead Author and Associate Professor, Biomedical Sciences, School of Medicine, University of California, Riverside
The family of proteins known as RELM, or resistin-like molecules, are produced by mammals and are widely expressed in inflammatory and infectious diseases.
Following infection, the mouse body swiftly activates one of these proteins, RELMalpha, which acts to defend the tissues of the body. Its sequence and functionality are similar to those of human resistin.
Nair added, “RELMalpha regulates two immune cell types: the anti-inflammatory macrophage and the eosinophil.”
White blood cells that fight sickness, such as eosinophils and macrophages, can harm the body when there is no infection.
She further stated, “In contrast, males expressed less RELMalpha, had less eosinophils, and had inflammatory macrophages that promoted obesity.”
Female mice that had RELMalpha deleted exhibited inflammatory macrophages identical to those of male mice, were no longer protected against obesity, and had fewer eosinophils.
Nair noted, “However, we were able to reduce obesity in these female mice by treating them with eosinophils or with RELMalpha, suggesting promising therapeutic targets. We are the first to map this pathway in females that protects against obesity.”
The study team discovered that males were also affected by RELMalpha deficiency, but less severely than females.
In our experiments, female mice had higher levels of RELMalpha than males, which likely explains why RELMalpha deficiency affected females more than males. The implications of our study are that consideration of sex differences is critical to tackle metabolic diseases such as obesity.
Djurdjica Coss, Study Co-Lead Author and Professor, Biomedical Sciences, School of Medicine, University of California, Riverside
The findings, according to Nair, are interesting in that it demonstrates a previously unknown role for RELMalpha in modifying metabolic and inflammatory responses during diet-induced obesity that is sex-dependent.
Nair further stated, “Our results highlight a critical ‘RELMalpha–eosinophil–macrophage axis’ that functions in females to protect from diet-induced obesity and inflammation. Promoting these pathways could, therefore, provide novel therapies for combating obesity.”
Li, J., et al. (2023). Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils. eLife. doi.org/10.7554/eLife.86001