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ACTRIMS 2021 | Leptin promotes inflammatory responses in obese MS patients

Jorge Correale, MD, Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires, Argentina, discusses several investigations looking into the association between obesity and multiple sclerosis (MS), as well as potential mechanisms behind this relationship. Several previous studies have identified an association between obesity and higher prevalence, or worse prognosis, of MS. To further investigate this, a cross-sectional study of over 300 patients and controls was conducted which analyzed serum leptin levels, expression of various T-cell lines and cytokines, and body weight at 15 and 20 years of age. Regression analysis showed that excess weight at age 15, and obesity at age 20 increased MS risk. It was also demonstrated that leptin increased proliferation and decreased apoptosis of autoreactive T-cells, inhibited regulatory T-cell proliferation, and promoted pro-inflammatory cytokine induction. These findings show how leptin is a significant part of the correlation between obesity and MS. This interview took place during the ACTRIMS Forum 2021.

Transcript (edited for clarity)

Basically, in their previous work that demonstrate that obesity in adolescent impact their risk to develop MS. And also that obesity have an impact in the course of MS. So, based in this previous study, we decided to…This study we are running in United States. So based on this study, we decided to check if in our population will see similar effect first.

And we did a survey with something like more than 300 patients and 300 controls to check with them what was their body weight at 15 and at 20, and after we calculated the risk of develop MS in this population...

Basically, in their previous work that demonstrate that obesity in adolescent impact their risk to develop MS. And also that obesity have an impact in the course of MS. So, based in this previous study, we decided to…This study we are running in United States. So based on this study, we decided to check if in our population will see similar effect first.

And we did a survey with something like more than 300 patients and 300 controls to check with them what was their body weight at 15 and at 20, and after we calculated the risk of develop MS in this population. Of course, our population is relatively small compared with previous study, where they studied thousands of patients. But I think we didn’t want to reproduce exactly the same work that previous article did. We have been more interested in trying to understand the mechanisms that can impact obesity in the development, or in the course of MS.

So, in the first part with this survey we demonstrated real risk. When you are overweight at 15 years old, you increase the risk of developing MS. If you are obese at 20 year old, you increase the risk to develop MS. So more or less we reproduced the data of other article. So with this data, we go to try to understand the role of the different substances that can be produced during obesity and have an impact in multiple sclerosis development and course.

So the fat tissue produces a series of hormones that are called adipokines, and there are different kinds of adipokines. To start, we choose one that is called leptin. We demonstrated that leptin had different effects. First of all, they decrease the apoptosis, the death of the autoreactive T-cells that are responsible of the disease. Second, they increase the proliferation of these autoreactive T-cells, and third they increase the production of cytokines that are responsible also for the development of MS.

By contrast, on the regulatory T-cells that are the cells that keep under control these autoreactive T-cells have an opposite effect. They decrease the proliferation of these regulatory T-cells, and induce impaired responsiveness of this particular group of cells that have the mission of control the autoreactive T-cells. So the balance between increase of the activity of autoreactive T-cells and decrease of the activity of the regulatory T-cells can explain why leptin have an important role in the development and in the course of MS in, always obesity playing a role through these particular hormone.

There are of course, many other things to do with it. There are at least another four or five different adipokines to try to study. We studied some of them in previous study, where we studied patients that have metabolic syndrome. In metabolic syndrome, arbitrarily the patient might have not only obesity, but also have another symptom like hypertension. We found that when you treat this patient with metformin, the metformin decreased the level of glycemia, you have the chance to produce an inversion in the level of leptins and an increase in the levels of adiponectin. Adiponectin have totally the opposite effect of leptin. This means that it decreased the reduction particularly of pro-inflammatory cytokine.

So this is something that is coming out, using metformin for the treatment. There are some clinical studies and some clinical phase-1 studies trying to explore the role of metformin, that is a drug that is in the market for years, to try to understand if metformin can be used to treat MS patients through these particular mechanisms.

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