Study may explain link between obesity, higher MS risk in women
Increased inflammation specific to females tied to greater MS susceptibility
Obesity promotes molecular signatures associated with more inflammation and multiple sclerosis (MS) signaling pathways specifically in females, which may explain the link between obesity and a higher risk of MS in women.
These are the findings of a new study analyzing data not only from obese and non-obese women and men, but also from a mouse model of MS, in which obesity was found to be linked to more severe disease and immune activation in females.
“We’re not clear why inflammation would affect one gender more than the other, but that inflammation seems to be what predisposes these women not only for MS, but also for other autoimmune diseases,” Bob Axtell, PhD, of the Oklahoma Medical Research Foundation (OMRF), and one of the study’s senior authors, said in an OMRF press release.
According to the study’s scientists, existing data point to adolescence as the critical period during which this effect starts to occur, so early lifestyle changes might be important for preventing MS in girls and women.
Overall, this work may also help explain why the autoimmune disease today is found in many more women than men, the team noted.
The study, “Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females,” was published in Cell Metabolism.
MS now affects many more women than men
MS is a chronic autoimmune disease characterized by the immune system’s self-reactive attacks on myelin, the substance that surrounds and protects nerve fibers.
Importantly, MS now disproportionately affects women over men, with about 80% of new MS cases occurring in female patients, according to the National Multiple Sclerosis Society. That sex difference was not as prominent a few decades ago, leading researchers to believe that changing environmental factors might play a role in the disparity.
One such factor is obesity, which has also been on the rise in recent decades, more than tripling in American children since the 1970s. Studies have indicated that childhood obesity increases the risk of MS, and that, according to Axtell, obesity in adolescence does so in females, but not in males. The mechanisms underlying that sex difference are poorly understood.
To learn more, the researchers performed a protein analysis on blood samples from men and women with relapsing-remitting MS (RRMS) and sex-matched people without MS, who were either obese or non-obese. In RRMS, relapses or exacerbations — periods of new or worsening symptoms — are followed by periods of remission in which symptoms ease.
Hundreds of proteins, 450 in total, were found at significantly increased levels in obese female RRMS patients relative to non-obese female patients, whereas only 51 proteins showed significantly higher levels with obesity in male patients. A similar obesity-associated pattern was observed in women and men without RRMS.
“Surprisingly, the majority of proteins that increased with obesity were distinct between men and women,” the researchers wrote, adding that “146 proteins were commonly [increased] with obesity in control and RRMS female groups.”
Investigators use mouse model to look at disease mechanisms
Signaling pathways that appeared to be increased in obese females were commonly associated with inflammation and MS-related processes.
To find out more about the mechanisms underlying these observations, the scientists turned to a mouse model of induced MS. They found that mice with diet-induced obesity experienced more severe MS symptoms than mice without it, and that this was especially prominent in females.
Moreover, female mice with diet-induced obesity exhibited a greater infiltration into the nervous system of several immune cell types upon MS induction relative to mice with a normal weight.
In particular, obese female mice showed increased growth and accumulation of pro-inflammatory Th1 cells — a type of immune cell implicated in MS — and related inflammatory molecules. These Th1 cells were specifically reactive to myelin proteins and appeared to be the driver of the more severe disease state experienced by obese female mice.
Altogether this profile, “mirrors the… inflammatory signatures detected in human females with obesity,” the researchers wrote.
We need to better understand the molecular underpinnings of this disease so that we can mitigate those factors before the onset of MS.
The inflammatory profile in female mice appeared to be driven in part by increased fat tissue as well as hormones produced in the ovaries.
Through a series of other experiments, the researchers identified that obesity led to increased levels of inflammatory signaling molecules called interferons being produced from naïve immune T-cells, which are not primed to launch an attack against anything in particular.
However, the increase in interferon molecules prompts the cells to mature into Th1 cells implicated in MS autoimmune attacks, thereby driving an increased disease severity in obese female mice.
Overall, the findings give researchers a better understanding of how obesity may drive MS specifically in female patients.
“We need to better understand the molecular underpinnings of this disease so that we can mitigate those factors before the onset of MS,” said Gabriel Pardo, MD, a study author at OMRF.
“But this study also provides a cautionary example pointing to another danger of obesity,” Pardo added.
Because the study showed an important role for both sex and weight in disease outcomes, both body mass index (a ratio of height and weight) and sex “should be considered in the design of clinical trials for the treatment of MS and other diseases,” the researchers wrote.
The study was funded by grants from the National Institute of Allergies and Infectious Diseases and the National Eye Institute, both part of the National Institutes of Health.
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