Obesity and a higher body mass index (BMI) are associated with both increased multiple sclerosis (MS) risk and harmful autoimmune activity that is induced by leptin, a hormone secreted by fat cells, a study finds.
These results indicate that leptin, which helps regulate body weight, may act as a functional link between obesity and MS.
The study, “Obesity and the risk of Multiple Sclerosis. The role of Leptin,” was published in the Annals of Clinical and Translational Neurology.
The worldwide prevalence of MS has increased over the past years, and previous studies have found a potential association between BMI and the risk of developing the disease — raising the possibility that increasing global obesity and MS cases may be related.
Obesity is known to promote chronic systemic inflammation, partially mediated by fat cells that secrete immune signaling proteins called cytokines, and can worsen immune disorders like MS. The hormone leptin plays a key role in regulating energy balance by inhibiting hunger and functions by binding to leptin receptors.
Leptin also is involved in the regulation of inflammatory and autoimmune responses, in which the body’s immune system mistakenly attacks its own cells. Because MS is considered an autoimmune disease, researchers now investigated if leptin is involved in regulating the autoimmune response in MS patients, thereby linking the disorder to BMI and obesity.
Based on the World Health Organization BMI definition, 162 MS patients (52.4%) and 145 healthy controls (45%) were normal weight or underweight. Meanwhile, 90 patients (29.1%) and 108 controls (33.5%) were overweight, and 57 patients (18.4%) and 69 controls (21.4%) were obese.
About three-fourths of the participants in both groups were women — a total of 229 MS patients (74.1%) and 247 controls (76.7%) — with a mean overall age in the two groups of 41.
Excess weight at age 15 and obesity at age 20 were both associated with an increased risk of developing MS. Specifically, the risk was 2.16 times higher for those who were overweight at age 15, and 3.9 times higher risk for those with obesity at age 20.
Moreover, in both MS patients and healthy controls, a higher BMI corresponded with higher blood levels of leptin, with obese patients having the highest leptin levels.
In several immune cell types, including T-cells, expression of the leptin receptor increases when the cells are activated. In autoreactive T-cells that cause autoimmunity, leptin was found to prevent the cells from undergoing programmed death, or apoptosis, in a dose-dependent manner. However, this effect disappeared when the leptin receptor was blocked, demonstrating that leptin activity prevents apoptosis in autoreactive T-cells and promotes a pro-inflammatory state.
In MS patients, BMI was found to be linked with the increased production of cytokine-secreting cells, such that obese people had the highest production. Moreover, when autoreactive T-cells from MS patients with normal weight were treated with leptin, they showed increased production of the same cytokines as cells from obese patients. Again, this effect was reversed by blocking the leptin receptor.
Meanwhile, among people with MS of normal weight, leptin levels were found to be negatively associated with the proportion of circulating regulatory T (Treg) cells that control autoimmune responses. Leptin treatment diminishes Treg cell growth and the production of new cells, and blocking the leptin receptor reverses this effect.
Importantly, Treg cells from MS patients blocked the production of autoreactive T-cells and their cytokine secretion, an effect that was diminished by the addition of leptin. Leptin’s suppressive effect on Treg cells was found to be influenced by factors that regulate new cell production and growth.
Taken together, these results suggest that leptin may favor autoreactive over regulatory T-cell activity.
“Leptin promotes autoreactive T‐cell proliferation and proinflammatory cytokine secretion,” while inhibiting Treg‐cell proliferation, the researchers wrote.
“Overall, the discovery of different pathways linking metabolism and autoimmunity allows a better understanding of the relationship between MS and certain life-style factors,” they wrote.
One limitation of the study is that data were not available for the study participants on other factors that may have contributed to childhood and adolescent obesity.
Thus, further studies are needed to address the link between obesity and leptin in MS.
“Further investigations will contribute to the development of new treatments, targeting improved energy balance modulation and ultimately better control over autoimmune diseases,” the researchers concluded.
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