Interleukin 6

Exercise Can Shrink Belly Fat, But Not When Drug Blocks IL-6

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Three months of stationary-bike endurance exercise training decreased abdominal visceral fat in obese patients, but not when they were also receiving tocilizumab (RoActemra, Roche), an antibody that blocks interleukin-6 (IL-6) receptors, in a new exploratory trial.

“To our knowledge, this is the first study to show that IL-6 has a physiological role in regulating visceral fat mass in humans,” said lead author Anne-Sophie Wedell-Neergaard, MD, PhD student, University of Copenhagen, Denmark, in a statement from her institution, released to coincide with publication of the study in Cell on December 27.

“We all know that exercise promotes better health,” she continued, “and now we also know that regular exercise training reduces abdominal fat mass and thereby potentially also the risk of developing cardiometabolic diseases.”

According to Wedell-Neergaard, physicians should tell patients “when you start exercising, you may increase body weight due to increased muscle mass. So, in addition to measuring your overall body weight, it would be useful, and maybe more important, to measure waist circumference to keep track of the loss of visceral fat mass and to stay motivated.”

This study also “raises a potentially important side effect of IL-6 receptor antibodies, such as tocilizumab” (that is, they block the belly-shrinking effect of exercise in obese patients), the researchers note.

Tocilizumab also increased total cholesterol and LDL-cholesterol compared with placebo both in participants in the “exercise” or “no-exercise” groups.

However, it remains to be seen whether these effects are also true for non-obese patients.

 

IL-6 and Waist Slimming Effect of Exercise

Abdominal adiposity with visceral fat surrounding internal organs, Wedell-Neergaard and colleagues write, is associated with increased risk of cardiometabolic disease, cancer, dementia, and earlier death.

On the other hand, exercise stimulates lipolysis, which is often attributed to the effect of epinephrine.

The researchers hypothesized that IL-6, which is released by skeletal muscles during exercise, may play a role in exercise-induced reductions in abdominal visceral tissue mass.

To test this, they randomized 67 physically inactive adults at their center who had a waist circumference of ≥ 88 cm for women or ≥ 102 cm for men to one of four groups:

  • No exercise plus placebo (18 patients)
  • No exercise plus tocilizumab (18 patients)
  • Exercise plus placebo (16 patients)
  • Exercise plus tocilizumab (15 patients)

Exercise consisted of several 45-minute supervised exercise-bike endurance training sessions per week for 12 weeks.

Tocilizumab (8 mg/kg body weight diluted in saline) and saline placebo were given as three monthly injections infused over 1 hour.

Five patients in each no-exercise group and two patients in each exercise group dropped out or did not adhere to the study protocol, leaving 53 patients for the data analysis.

Patients were a mean age of 44 years and had a mean body mass index of 33 kg/m2. Three quarters (40/53) of participants were women.

Researchers measured visceral fat mass using MRI at the beginning and end of the study.

After 12 weeks, visceral fat mass was reduced by 225 g, or 8%, in the exercise plus placebo group compared with the no exercise plus placebo group.

The 8% reduction in visceral adipose tissue with exercise was lower than the 15% to 20% reductions reported in other studies, likely because of longer exercise sessions in the other studies, the researchers suggest.

There was no exercise-induced decrease in visceral tissue mass, however, when patients received the IL-6 blocker tocilizumab. Rather, visceral adipose tissue increased by 278 g more in the exercise plus tocilizumab group than in the exercise plus placebo group.

However, IL-6 blockade did not affect improvements in cardiorespiratory fitness, which were the same in both exercise groups.

This is an exploratory study, the authors caution, with a small number of participants. Nevertheless, the findings were consistent for both sexes.

In addition, chronic low-grade elevations of IL-6 are seen in patients with severe obesity, type 2 diabetes, and cardiovascular disease, the researchers note, so it is “likely that IL-6 may act differently in healthy and diseased people.”

Nevertheless, “this study has consolidated a physiological role of IL-6 as a lipolytic factor in humans with abdominal obesity and highlights a potentially important metabolic consequence of IL-6 blockade.”

“It remains to be clarified,” they conclude, “whether IL-6 regulates visceral adipose tissue mass in humans with all waist circumferences.”

Cancer cell enzymes shown to act as ‘good cops.

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Enzymes released by cancerous cells have a protective function and are not one of the “bad guys”, say researchers from the University of East Anglia.

Their study found the MMP-8 enzyme sent a signal to the immune system to attack the tumour.

Patients whose breast tumours have more of this enzyme seem to do better.

Cancer Research UK said the research provided “very early clues” as to how the enzyme might recruit cells to fight breast cancer.

Scientists from UEA worked with clinicians at the Norfolk and Norwich University Hospital to look in detail at the patterns of MMPs in breast tumours from patients.

Their study, published in the Journal of Biological Chemistry, reveals that the matrix metalloproteinase-8 enzyme (MMP-8) could be acting as the ‘good guy’ by alerting the immune system to the location of the tumour.

It had been thought that the production of MMPs by breast cancer cells helped to promote cancer growth.

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MMP-8 acts as a sort of ‘find me’ signal to the immune system, which then becomes activated to attack the tumour”

Prof Dylan Edwards, lead researcher from UEA’s School of Biological Sciences, said that if breast cancer cells produce MMP-8 it causes them to produce two other inflammatory factors (IL-6 and IL-8) that have previously been shown to promote cancer.

“They were once thought to act like ‘molecular scissors’ to snip away at the scaffolding structures outside cells and clear a path for the cancer cells to invade and spread to other organs.

“However, breast tumour cells that over-produce MMP-8 don’t survive long-term – the enzyme stops them growing,” he said.

“We now think that in tumours, MMP-8 acts as a sort of ‘find me’ signal to the immune system, which then becomes activated to attack the tumour, which may help to explain its protective function.”

Drugs used to treat cancer in the 1990s, which blocked these enzymes, failed in the clinic, he said, and this new research may explain why.

It is still not known exactly how MMP-8 causes IL-6 and IL-8 to be activated.

Finding this out will be an important step forward which will help direct further research.

Dr Emma Smith, senior science information officer at Cancer Research UK, said: “This study provides very early clues as to how the MMP-8 protein might actually play the role of a ‘good cop’ and recruit immune cells to fight breast cancer.

“And, rather than seeing the MMP-8 protein as a ‘bad cop’ in breast cancer, recent research has shown that levels of this protein are raised in women who do relatively well.

“Yet, until now, we haven’t known why this should be the case.

“But these are early findings from cells grown in a lab, and more research is needed to see if the molecules found by the scientists alert immune cells to cancers in women.”

Source: BBC