Anti-inflammatory effect of exercise training through reducing inflammasome activation-related inflammatory cytokine levels in overweight/obese populations: A systematic review and meta-analysis

The prevalence of obesity has increased worldwide in the past several decades, and become a major concern for public health [1,2]. One-third of the world's adult population is either overweight (body mass index (BMI) 25–29.9 kg/m2) or obese (BMI ≥30 kg/m2), and children and adolescents are becoming obese at a younger age [3,4]. Obesity is a strong risk factor for various pathological conditions, such as type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), cardiovascular and neurodegenerative diseases, and several types of cancer [5,6]. A chronic low-grade inflammation state is observed in obesity and may have a role in the pathogenesis of obesity-related diseases [[7], [8], [9], [10]]. Studies have suggested that alleviating inflammation can be a therapeutic strategy for obesity and obesity-related diseases [5,11].

Obesity-induced inflammation involves multiple organs, including adipose tissue, liver, skeletal muscle, heart, brain and pancreas [9]. In populations with obesity, hypertrophic adipocytes and tissue infiltrating immune cells undergo phenotypic and functional changes that switch from secreting anti-inflammatory cytokines to pro-inflammatory adipokines and cytokines, thus inducing systemic inflammation [5,7]. The underlying mechanisms are still unclear, however, recent studies have found that inflammasome activation plays an important role in obesity-induced inflammation [[12], [13], [14]]. Inflammasomes are multimolecular protein complexes that assemble in response to a variety of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs) [12,13,15]. The initiation of inflammasome signaling leads to the activation of caspase-1, which further cleaves immature pro-interleukin (IL)-1β and pro-IL-18 to become biologically active cytokines IL-1β and IL-18 [12,13,15]. Several inflammasomes including nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP) 1, NLRP3, and absent in melanoma 2 (AIM2) have been studied in humans and animals [12,13,15]. Previous studies demonstrated that the expression of NLRP3 inflammasome, the activity of caspase-1, and the levels of IL-1β and IL-18 were increased in adipose tissue of obese individuals compared with non-obese control, and the level of inflammasome activation was positively correlated with the severity of insulin resistance, metabolic syndrome and T2DM [10,16]. Inhibition of NLRP3 reduced the secretion of pro-inflammatory cytokines and enhanced insulin signaling [14,17]. The pro-inflammatory cytokine IL-1β interacts with the IL-1 receptor-I and leads to the activation of NF-κB pathways and the production of other pro-inflammatory cytokines, and has been found to promote the pathogenesis of T2DM [10,18]. Furthermore, IL-18 acts through the IL-18 receptor to induce intracellular signal transduction, which promotes the maturation of T cells and natural killer cells as well as the production and secretion of other pro-inflammatory cytokines, chemokines, and cell adhesion molecules [16]. Thus, strategies can be developed to target these two end-products of inflammasome activation signaling to reduce inflammation in obesity and obesity-related diseases.

Dietary modification and physical activity are two of the most common and important strategies in the prevention and treatment of obesity [19,20]. Exercise training can reduce chronic inflammation in people with obesity [21,22]. Several mechanisms have been suggested. Regular exercise could decrease the production and secretion of pro-inflammatory adipokines by reducing the size of adipose tissue [23]. Exercise training without weight loss is still effective in reducing inflammation [21]. The infiltration of immune cells such as macrophages into the adipose tissue could be suppressed and the phenotypic switching from pro-inflammatory M1 to anti-inflammatory M2 macrophages in adipose tissue could be accelerated through regular exercise [24]. In addition, exercise could promote muscle tissue to generate muscle-derived, anti-inflammatory myokines, improve hypoxia in hypertrophic adipocytes, and reduce leukocyte adhesion and cytokine production of endothelial cells [21,25,26]. However, whether regular exercise can regulate inflammation in overweight/obese populations through the inflammasome activation signaling remains unclear.

In the present systematic review and meta-analysis, we aimed to investigate the effect of exercise training on circulating levels of inflammasome activation-related inflammatory cytokines IL-1β and IL-18 in overweight/obese populations. Randomized controlled trials (RCTs) with participants that were generally healthy, with BMI ≥25 kg/m2 (average BMI) but without any other diseases that may confound the response to exercise were selected. Subgroup analyses were also performed to evaluate the effect of exercise in susceptible populations and to find the best training strategy.

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