Multiple sclerosis (MS) is an autoimmune disease in which the immune system attacks the central nervous system (CNS), leading to nerve damage. T-cells play a central role in this process by producing inflammatory molecules that destroy the myelin sheaths of nerve fibers.
In women with obesity, specific immune pathways are activated, enhancing inflammation in the CNS. This process leads to a more aggressive course of MS. Obese women also exhibit higher levels of the pro-inflammatory interferon-α (IFN-α), which may explain their predisposition to autoimmune diseases.
Obesity Differentially Affects Pro-inflammatory Pathways in Men and Women
In women with MS who are also obese, significantly more inflammatory proteins were found compared to men. Women showed elevated levels of 450 inflammatory proteins, whereas men had an increase of only 51. Interestingly, most proteins that increased with obesity differed between men and women. The only protein that increased with obesity across all participants, regardless of gender or presence of MS, was leptin—a hormone produced by adipose tissue that regulates appetite.
In women with obesity, several inflammatory pathways were amplified: cytokine storm, Th1, IL-17, IL-6, dendritic cell maturation, and MS signaling pathways. These data suggest that obesity may play a crucial role in the development of inflammatory processes in MS, especially in women.
Diet-induced Obesity Worsens the Severity of Autoimmune Encephalomyelitis in Female Mice
Researchers experimented on mice, feeding them a high-fat diet for four weeks, which led to weight gain. The mice were then induced with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Obesity worsened the severity of the disease in both sexes but was particularly pronounced in females. In the central nervous system of female mice, there was a significant increase in the number of pro-inflammatory CD4 T-cells producing IFN-γ, which led to more severe inflammation and myelin damage. When T-cells were transferred from obese female mice to healthy mice, these cells induced more severe EAE.
Increased T-cell Response in Female Mice Linked to Weight Gain
The gut microbiome can influence immune responses. Although a high-fat diet altered the microbiome composition, the sex of the mice did not significantly impact these changes, indicating that inflammatory response differences in EAE were unrelated to the microbiome. Instead, weight gain was key in enhancing inflammation and the autoimmune response.
Inflammation Induced by Obesity Is Driven Not by Leptin but by Ovarian Hormones
Diet-induced obesity differently affected female and male mice. Despite males gaining more weight, the females exhibited heightened T-cell-related inflammatory processes. Obese females exhibited heightened activity of Th1 cells that produce pro-inflammatory IFN-γ, with the increase not solely attributed to weight gain but also influenced by female sex hormones; removing the ovaries reduced the inflammatory response.
The increased T-cell activity observed in obese female mice with short-term obesity was reversible and decreased with weight loss. Interestingly, despite the elevated leptin levels in obesity, its impact on IFN-γ production by T-cells was negligible.
Obesity Stimulates Type I Interferon Response, Leading to More Severe Autoimmune Encephalomyelitis
The inflammation caused by increased T-cell activity was associated with elevated blood levels of interferon-α in obese female mice. Unlike males, who did not show such an increase in IFN-α, females exhibited enhanced activation of the STAT1 protein and increased IFN-γ production by T-cells.
To verify the role of IFN-α, researchers created mice deficient in the IFNAR receptor, responsible for IFN-α signal transmission. In these mice, inflammation was significantly reduced. IFNAR deficiency protected the mice from worsening autoimmune encephalomyelitis typically seen with obesity. Thus, IFN-α signaling is a crucial mechanism that enhances inflammation in obese female mice.
Conclusion
The incidence of multiple sclerosis has significantly increased over recent decades, particularly among women with obesity and a genetic predisposition. In obese women, immune cell activity increases, associated with elevated levels of interferon-α. IFN-α signaling amplifies inflammation and promotes autoimmune reactions. Unlike men, this leads to more pronounced STAT1 protein activation in women, intensifying T-cell responses to infections and contributing to the development of multiple sclerosis. Therefore, when developing treatment methods for multiple sclerosis and other autoimmune diseases, it is crucial to consider the patient’s gender and body mass index.
Useful article, necessary information? Share it!
Someone will also find it useful and necessary:
