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Developmental Biology - Interleukin-6

How Exercise Reduces Belly Fat

The signaling molecule Interleukin-6 is critical in reducing belly fat...

Some of us made a New Year's resolution to tackle annoying belly fat. But how does physical activity reduce fat? A signaling molecule called interleukin-6 plays a critical role in the process, as reported December 27 in the journal Cell Metabolism.

As expected, a 12-week intervention consisting of bicycle exercise decreased visceral abdominal fat in obese adults. But remarkably, this effect was abolished in participants who were also treated with tocilizumab, a drug that blocks interleukin-6 signaling and is currently approved for the treatment of rheumatoid arthritis. Moreover, tocilizumab treatment increased cholesterol levels regardless of physical activity.
"The take home for the general audience is 'exercise'. We all know that exercise promotes better health, and now we also know that regular exercise training reduces abdominal fat mass and thereby potentially also the risk of developing cardio-metabolic diseases."

Anne-Sophie Wedell-Neergaard PhD, The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark and first author.

Abdominal fat can increase risk of not only cardio-metabolic disease, but also cancer and dementia. All causes of mortality. Physical activity reduces visceral fat surrounding internal organs in the abdomen, but understanding mechanisms for why this happens are still unclear. Some research proposes the "fight-or-flight" hormone epinephrine mediates this effect. But Wedell-Neergaard and co-senior author Helga Ellingsgaard PhD, University of Copenhagen, suspect that interleukin-6 could also play an important role as it regulates energy metabolism, stimulates the breakdown of fats in healthy people, and is released from skeletal muscle during exercise.

To test their idea, they carried out a 12-week, single-center trial to randomly assigned abdominally obese adults in four groups. Fifty-three participants received intravenous infusions of either tocilizumab or saline as a placebo - every four weeks, combined with no exercise or a bicycle routine of several 45-minute sessions each week. Researchers used magnetic resonance imaging (MRI) to assess fat tissue mass at the beginning and end of the study.

In the placebo groups, exercise reduced visceral fat tissue mass by an average of 225 grams, or 8 percent, compared with no exercise. But tocilizumab treatment eliminated this effect. In the exercise groups, tocilizumab also increased visceral fat tissue mass by approximately 278 grams compared with placebo. In addition, tocilizumab increased total cholesterol and "bad" low-density-lipoprotein (LDL) cholesterol compared with placebo, in both the exercise and no-exercise groups.
"To our knowledge, this is the first study to show that interleukin-6 has a physiological role in regulating visceral fat mass in humans."

Anne-Sophie Wedell-Neergaard PhD, The Centre of Inflammation and Metabolism; Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark

The authors point out the study is exploratory and not intended as an evaluation of a given treatment in a clinical setting. Interleukin-6 can have what seems to be opposite effects on inflammation, depending on the tissue and the patient. For example, chronic low-grade elevations of interleukin-6 are seen in patients with severe obesity, type 2 diabetes, and cardiovascular disease.
"Signaling pathways in immune cells versus muscle cells differ substantially, resulting in pro-inflammatory and anti-inflammatory actions, so interleukin-6 may act differently in healthy and diseased people."

Anne-Sophie Wedell-Neergaard PhD

In future studies, researchers will test the possibility that interleukin-6 affects whether fats or carbohydrates are used to generate energy under varying conditions. They will also investigate whether more interleukin-6, given as an injection, reduces visceral fat mass on its own. "We need a more in-depth understanding of this role of interleukin-6 in order to discuss its implications," Wedell-Neergaard says. In the meantime, the authors have some practical holiday exercise tips.
"It's important to stress when you start exercising, you may increase body weight from increasing your muscle mass. So, in addition to measuring your overall body weight, it may be more important to measure waist circumference to keep track of loss of visceral fat mass and to stay motivated."

Anne-Sophie Wedell-Neergaard PhD

• Exercise reduces visceral adipose tissue mass
• Loss of visceral adipose tissue mass following exercise is dependent on IL-6
• IL-6 receptor blockade increases total cholesterol and is not influenced by exercise
• Improvements in cardiorespiratory fitness following exercise are not IL-6 dependent

Visceral adipose tissue is harmful to metabolic health. Exercise training reduces visceral adipose tissue mass, but the underlying mechanisms are not known. Interleukin-6 (IL-6) stimulates lipolysis and is released from skeletal muscle during exercise. We hypothesized that exercise-induced reductions in visceral adipose tissue mass are mediated by IL-6. In this randomized placebo-controlled trial, we assigned abdominally obese adults to tocilizumab (IL-6 receptor antibody) or placebo during a 12-week intervention with either bicycle exercise or no exercise. While exercise reduced visceral adipose tissue mass, this effect of exercise was abolished in the presence of IL-6 blockade. Changes in body weight and total adipose tissue mass showed similar tendencies, whereas lean body mass did not differ between groups. Also, IL-6 blockade increased cholesterol levels, an effect not reversed by exercise. Thus, IL-6 is required for exercise to reduce visceral adipose tissue mass and emphasizes a potentially important metabolic consequence of IL-6 blockade.

Anne-Sophie Wedell-Neergaard, Louise Lang Lehrskov, Regitse Højgaard Christensen, Grit Elster Legaard, Emma Dorph, Monica Korsager Larsen, Natja Launbo, Sabrina Ravn Fagerlind, Sidsel Kofoed Seide, Stine Nymand, Maria Ball, Nicole Vinum, Camilla Noerfelt Dahl, Marie Henneberg, Mathias Ried-Larsen, Janus Damm Nybing, Robin Christensen, Jaya Birgitte Rosenmeier, Kristian Karstoft, Bente Klarlund Pedersen, Helga Ellingsgaard, Rikke Krogh-Madsen.

This study was funded by TrygFonden.

Institutions involved in this research:
1) The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
2) Department of Radiology, Copenhagen University Hospital Bispebjerg, 2400 Copenhagen, Denmark
3) Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg and Frederiksberg Hospital, 2000 Copenhagen, Denmark
4) Department of Rheumatology, Odense University Hospital, 5000 Odense, Denmark
5) Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, 2400 Copenhagen, Denmark.

Cell Metabolism (@Cell_Metabolism), published by Cell Press, is a monthly journal that publishes reports of novel results in metabolic biology, from molecular and cellular biology to translational studies. The journal aims to highlight work addressing the molecular mechanisms underlying physiology and homeostasis in health and disease. Visit: http://www.cell.com/cell-metabolism. To receive Cell Press media alerts, contact press@cell.com.

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Jan 2, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

This graphic shows that in abdominally obesity, exercise-mediates loss of visceral fat,
but requires IL-6 receptor signaling. Image: Wedell-Neergaard et al/ Cell Metabolism.

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