Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning, redistribution of energy substrates, optimization of global energy expenditure, enhancement of hypothalamic circuits that control appetite-satiety and energy expenditure, and decreased systemic inflammation and insulin resistance. Novel exercise-inducible soluble factors, including myokines, hepatokines, and osteokines, and immune cytokines and adipokines are hypothesized to play an important role in the body’s response to exercise. To our knowledge, no review has provided a comprehensive integrative overview of these novel molecular players and the mechanisms involved in the redistribution of metabolic fuel during and after exercise, the loss of weight and fat mass, and reduced inflammation. In this review, we explain the potential role of these exercise-inducible factors, namely myokines, such as irisin, IL-6, IL-15, METRNL, BAIBA, and myostatin, and hepatokines, in particular selenoprotein P, fetuin A, FGF21, ANGPTL4, and follistatin. We also describe the function of osteokines, specifically osteocalcin, and of adipokines such as leptin, adiponectin, and resistin. We also emphasize an integrative overview of the pleiotropic mechanisms, the metabolic pathways, and the inter-organ crosstalk involved in energy expenditure, fat mass loss, reduced inflammation, and healthy weight induced by exercise.

Proinflammatory cytokines and the novel myokine irisin, a cleavage product of FNDC5, have been found to play a role in obesity and type 2 diabetes mellitus (T2DM). Irisin has been shown to increase browning of adipose tissue, thermogenesis, energy expenditure, and insulin sensitivity, yet its association with inflammatory markers is still limited. Circulating irisin has been found to be increased in obesity, while in adult subjects with T2DM decreased levels have been found. However, data establishing the association of circulating irisin in children and adolescents with T2DM has not been described in the literature. The objective of this study was to determine irisin plasma concentration and its association with metabolic and adiposity markers and with hs-CRP, a surrogate marker of inflammation used in clinical practice, in a pediatric population with T2DM. A cross-sample of 40 Mexican children and adolescents aged 7-17 were recruited, 20 diagnosed with T2DM and 20 healthy controls. Plasma irisin levels were found to be lower in the T2DM group compared with controls, which could be attributed to a reduced PGC-1α activity in muscle tissue with a consequent decrease in FNDC5 and irisin expression. Irisin concentration was found to be positively correlated with HDL-c, LDL-c, and total cholesterol, while negatively correlated with BMI, waist circumference, and triglycerides. However, after multiple regression analysis, only HDL-c correlation remained significant. hs-CRP was higher in the T2DM group and positively associated with adiposity markers, unfavorable lipid profile, insulin levels, and HOMA-IR, but no association with irisin was found. Given the favorable metabolic effects attributed to irisin, the low plasma levels found in children and adolescents with T2DM could exacerbate the inflammatory and metabolic imbalances and the intrinsic cardiovascular risk of this disease. We propose an “irisin-proinflammatory/anti-inflammatory axis” to explain the role of irisin as a metabolic regulator in obesity and T2DM.

Vitamin D deficiency is highly prevalent worldwide. It has been associated with heart failure (HF) given its immunoregulatory functions. In-vitro and animal models have shown protective roles through mechanisms involving procollagen-1, JNK2, calcineurin/NFAT, NF-κB, MAPK, Th1, Th2, Th17, cytokines, cholesterol-efflux, oxLDL, and GLUT4, among others. A 12-month follow-up in HF patients showed a high prevalence of vitamin D deficiency, with no seasonal variation (64.7–82.4%). A positive correlation between serum 25(OH)D concentration and dietary intake of vitamin D-rich foods was found. A significant inverse correlation with IL-1β (R = −0.78), TNF-α (R = −0.53), IL-6 (R = −0.42), IL-8 (R = −0.41), IL-17A (R = −0.31), LDL-cholesterol (R = −0.51), Apo-B (R = −0.57), total-cholesterol (R = –0.48), and triglycerides (R = −0.32) was shown. Cluster analysis demonstrated that patients from cluster three, with the lowest 25(OH)D levels, presented the lowermost vitamin D intake, IL-10 (1.0 ± 0.9 pg/mL), and IL-12p70 (0.5 ± 0.4 pg/mL), but the highest TNF-α (9.1 ± 3.5 pg/mL), IL-8 (55.6 ± 117.1 pg/mL), IL-17A (3.5 ± 2.0 pg/mL), total-cholesterol (193.9 ± 61.4 mg/dL), LDL-cholesterol (127.7 ± 58.2 mg/dL), and Apo-B (101.4 ± 33.4 mg/dL) levels, compared with patients from cluster one. Although the role of vitamin D in the pathogenesis of HF in humans is still uncertain, we applied the molecular mechanisms of in-vitro and animal models to explain our findings. Vitamin D deficiency might contribute to inflammation, remodeling, fibrosis, and atherosclerosis in patients with HF.

Background Adipokines and the myokine irisin, involved in mechanisms associated with obesity and metabolic syndrome (MS), are understudied in the pediatric population. Objective To investigate the relationship between irisin, and leptin, resistin, adiponectin, adipsin, anthropometric and cardiovascular risk factors in Mexican children. Methods A cross-sample of 126 Mexican children aged 6–12 years old were classified as normal weight (n = 46), obese (n = 40), and MS (n = 40) according to CDC’s and Cook’s age-modified criteria for obesity and MS. Anthropometric parameters and blood pressure were determined and percentiles calculated for age and gender. Irisin, leptin, adiponectin, adipsin, resistin, triglycerides, glucose, high-density lipoprotein cholesterol (HDL-c) levels, and physical activity were determined. Statistical tests for differences between groups, correlation, and multiple regression analyses were performed. Results Irisin plasma levels were significantly lower in the obese (6.08 [4.68–6.65]) and MS groups (6.46 [5.74–7.02]) compared with the normal-weight group (8.05 [7.24–8.94]) (p < 0.001). Irisin levels were not influenced by age or gender, but significant dispersion was observed in obese girls (95% CI median [2.29–6.30]). Leptin, resistin, and adipsin levels were significantly increased in the obese and MS groups. Lean-fat ratio was significantly higher in the NW group. Irisin correlated negatively with leptin (− 0.310), resistin (− 0.389), adipsin (− 0.362), BMI% (-0.472), WC% (− 0.453), BMI z-score (− 0.496), fat free mass (− 0.257), fat percentage (− 0.532), fat mass (− 0.515), triglycerides (− 0.291), the number of cardiometabolic risk factors (− 0.443) (p < 0.001); positively with lean-fat ratio (0.489) and HDL-c (0.328) (p < 0.001) and none with physical activity ( p < 0.001). Following stepwise multiple linear regression analysis, the lean-fat ratio was the only determinant of irisin levels (B = 1.168, p < 0.001). Conclusions Lean-fat ratio, more than the absolute amount of muscle or fat mass, as well as potential myokine–adipokine cross-talk mechanisms may explain the lower irisin levels in children with obesity and MS, through blunted compensatory responses interfering with tissue-dependent irisin secretion, contributing to a continuous deleterious effect cycle. Electronic supplementary material The online version of this article (10.1186/s13098-019-0458-2) contains supplementary material, which is available to authorized users.

Despite numerous demonstrations that the immune system is activated in heart failure, negatively affecting patients' outcomes, no definitive treatment strategy exists directed to modulate the immune system. In this review, we present the evidence that B cells contribute to the development of hypertrophy, inflammation, and maladaptive tissue remodelling. B cells produce antibodies that interfere with cardiomyocyte function, which culminates as the result of recruitment and activation of a variety of innate and structural cell populations, including neutrophils, macrophages, fibroblasts, and T cells. As B cells appear as active players in heart failure, we propose here novel immunomodulatory therapeutic strategies that target B cells and their products.

The prevalence of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has increased in the pediatric population. Irisin, an adipomyokine, is involved in white adipose tissue browning, energy expenditure, insulin sensitivity, and anti-inflammatory pathways. Data on the associations among circulating irisin levels, soluble cell adhesion molecules (sCAMs), and inflammatory cytokines is scarce in children and adolescents with MetS and T2DM. Subjects aged 6-16 years were grouped into T2DM, MetS, and healthy controls. Serum irisin levels were significantly lower in the MetS (6.6 [2.8-18.0] ng/mL) and T2DM (6.8 [2.2-23.2] ng/mL) groups compared with controls (30.3 [24.6-57.1] ng/mL). Negative correlations between irisin and the BMI percentile (R=−0.358), WC percentile (R=−0.308), and triglycerides (R=−0.284) were identified, while positive associations with TC (R=0.287), HDL-c (R=0.488), and LDL-c (R=0.414) were observed. Significant negative correlations were found between irisin and sNCAM (R=−0.382), sICAM-2 (R=−0.300), sVCAM-1 (R=−0.292), MCP-1 (R=−0.308), and IFN-α2 (R=−0.406). Of note, lower concentrations of most sCAMs (sICAM-1, sPSGL-1, sP-selectin, sEpCAM, sICAM-2, sALCAM, sPECAM-1, sCD44, sVCAM-1, sICAM-3, sL-selectin, and sNCAM) were shown in T2DM subjects compared with MetS patients. Lower irisin levels induce a lack of inhibition of oxidative stress and inflammation. In T2DM, higher ROS, AGEs, glucotoxicity, and inflammation trigger endothelial cell apoptosis, which downregulates the sCAM expression as a compensatory mechanism to prevent further vascular damage. In opposition, in subjects with MetS that have not yet developed T2DM and its accompanying stressors, the upregulation of the sCAM expression is ensued.

Endothelial dysfunction is a crucial physiopathological mechanism for cardiovascular diseases that results from the harmful impact of metabolic disorders. Irisin, a recently discovered adipomyokine, has been shown to exert beneficial metabolic effects by increasing energy consumption, improving insulin sensitivity, and reducing the proinflammatory milieu. Multiple preclinical models have assessed irisin's possible role in the development of endothelial dysfunction, displaying that treatment with exogenous irisin can decrease the production of oxidative stress mediators by up-regulating Akt/mTOR/Nrf2 pathway, promote endothelial-dependent vasodilatation through the activation of AMPK-PI3K-Akt-eNOS pathway, and increase the endothelial cell viability by activation of ERK proliferation pathway and downregulation of Bad/Bax/Caspase 3 pro-apoptotic pathway. However, there is scarce evidence of these mechanisms in clinical studies, and available results are controversial. Some have shown negative correlations of irisin levels with the burden of coronary atherosclerosis and leukocyte adhesion molecules' expression. Others have demonstrated associations between irisin levels with increased atherosclerosis risk and higher carotid intima-media thickness. Since the role of irisin in endothelial damage remains unclear, in this review, we compare, contrast, and integrate the current knowledge from preclinical and clinical studies to elucidate the potential preventive role and the underlying mechanisms and pathways of irisin in endothelial dysfunction. This review also comprises original figures to illustrate these mechanisms.

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