#ACTRIMS2021 – Leptin’s Pro-inflammatory Effects May Link Obesity to MS

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The fat-related hormone leptin has pro-inflammatory effects on immune cells, new data show, findings that help in better understanding the connection between obesity and multiple sclerosis (MS).

These data were presented at the virtual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021, by Jorge Correale, MD, at the Raúl Carrea Institute for Neurological Research in Buenos Aires, Argentina. His presentation was titled “The Relationship Between Obesity and MS, Metabolic-Immunological Interactions.”

MS is caused by the immune system erroneously launching an inflammatory attack against healthy tissue in the nervous system. Obesity is a well-established risk factor for MS; however, the exact biological mechanisms that connect MS and obesity are incompletely understood.

Leptin is an adipokine, a hormone that is secreted by adipose (fat) tissue. It exerts its effects on cells by binding to a cellular protein receptor, called the leptin receptor.

Leptin levels are typically elevated in obese people. This hormone has well-known functions in regulating metabolism and hunger, but emerging research shows that it also affects the immune system.

Correale and his colleagues investigated the effects of leptin on specific immune T-cells in an attempt to better understand the mechanisms linking obesity and MS.

First, they surveyed 309 people with relapsing-remitting MS (RRMS) and 322 controls (people without MS); both groups were similar in terms of age, sex, and other demographic factors.

Participants were classified into three groups based on their body mass index (BMI): normal/underweight [18.5 to less than 24.9 kilograms per square meter (kg/m2) for normal weight, and less than 18.5 kg/m2 for underweight], overweight (25 to less than 30 kg/m2), and obesity (more than 30 kg/m2) groups. (BMI is a ratio of weight to height, a general measure of body fat.)

In line with prior data, people overweight at age 15 were more than twice as likely to develop MS, and those who were obese at age 20 were nearly four times more likely, analyses showed.

“Obesity in adolescence/early adulthood is associated with [an] increased risk of MS,” Correale said.

The researchers also demonstrated that leptin levels correlated with BMI. In other words, heavier individuals tended to have higher leptin levels, which is also consistent with prior data.

Obese individuals also had generally higher levels of pro-inflammatory signaling molecules called cytokines, again consistent with previous research findings.

Researchers then investigated the effects of leptin on T-cells, a type of immune cell. Specifically, they looked at two kinds of T-cells: effector T-cells and regulatory T-cells (Tregs).

Effector T-cells are pro-inflammatory T-cells — in the context of MS, these cells help to drive the immune system’s attack on the nervous system. In contrast, Tregs act to lessen inflammation, mainly by secreting anti-inflammatory signaling molecules.

When both types of T-cells become activated, they increase their expression of the leptin receptor, the researchers found. Other kinds of immune cells, namely B-cells and monocytes, also increased expression of the leptin receptor upon activation.

In experiments using cell lines, treating effector T-cells with leptin prompted these cells to proliferate (divide). Leptin treatment also reduced apoptosis (programmed cell death) of effector T-cells, and these cells produced more inflammatory cytokines.

In contrast, leptin treatment lessened the proliferation of Tregs. The researchers found an inverse correlation between leptin levels and levels of circulating Tregs, meaning that individuals with higher leptin levels would tend to have fewer Tregs.

Of note, when researchers blocked the leptin receptor, the effects of leptin on both effector T-cells and Tregs were also blocked, indicating that the hormone was affecting these cells directly by binding to its receptor.

In other in vitro cell experiments, effector T-cells and Tregs were placed together in the same cell culture dish. This led to decreased proliferation and inflammatory cytokine secretion by effector T-cells, due to the anti-inflammatory effects of Tregs.

However, when researchers added leptin to these cells, effector T-cell proliferation and cytokine secretion increased, approaching levels found in the absence of Tregs.

“When we add leptin to the [cell] culture, we can overcome the effect of the regulatory T-cells, indicating that leptin inhibits the function of the regulatory T-cells,” Correale said.

Based on these data, Correale concluded that “leptin promotes opposite effects on regulatory and effector T-cells.”

Researchers found that, in effector T-cells, leptin led to the activation of STAT3 and ERK1/2, proteins that play central roles in promoting T-cell activity, and to a decrease in the levels of P27-kip1, a protein that acts to stop cell division.

With Tregs, in contrast, leptin reduced ERK1/2 activation and increased the levels of P27-kip1.