ABC | Volume 113, Nº6, December 2019

Review Article Ferrari et al. Exercise-mediated glucose uptake Arq Bras Cardiol. 2019; 113(6):1139-1148 dysfunction induced by inflammation, which in turn aggravates the chronic inflammatory process. 86 This feedback causes more macrophage recruitment, which together with hypertrophic adipocytes, release more pro-inflammatory cytokines. 87 Additionally, circulating free fatty acids, as well as other ligands such as bacterial lipopolysaccharides, are able to activate transmembrane proteins known as toll-like receptor 4 (TLR-4), that trigger inflammatory pathways, reducing glucose uptake by insulin signaling 88 in a process called metabolic inflammation. 89 TLR-4 is ubiquitously expressed throughout the cells, including the adipose tissue. In the development of obesity, there is greater infiltration of immune cells in this tissue, particularly macrophages, which show increased expression of TLR4. 90 Free fatty acids bind to TLR-4, activating JNK and I κ B kinase (IKK). 91 Because IRS-1 are target of both enzymes, this process affects tyrosine phosphorylation, resulting in reduced GLUT4 translocation. 92 Activation of IKK causes phosphorylation and subsequent proteasomal degradation of IKK β , inducing activation of NF- κ B. Degradation of IKK β triggers the gene transcription of inflammatory mediators, such as TNF- α and interleukin-6 (IL-6). 93 Also, IKK β promotes serine phosphorylation of insulin receptor and IRS-1 and IRS-2 substrates, which reduces insulin signaling in different tissues. 94 These processes are schematically illustrated in Figure 2. In summary, the increase in circulating free fatty acids is a metabolic characteristic of insulin-resistant state, which may cause IR by several mechanisms. Evidence has suggested that excess adipose tissue reduces insulin receptor phosphorylation and promotes chronic activation of pro-inflammatory cytokines and circulating fatty acids, which may lead to deterioration of the tissue response to insulin. Adipose tissue, previously believed to be a mere place of energy storage, has shown to be an important endocrine and pro-inflammatory organ. It is more evident with visceral white adipose tissue that exhibits macrophage infiltration with local production of interleukins, which can help in the development of local and systemic IR. 95‑97 Therefore, strategies targeting anti-inflammatory responses in the adipose tissue, such as PE, may have beneficial effects on individual’s health status, alleviating the burden of obesity in endocrine dysregulation. Physical exercise in obesity and insulin resistance The beneficial role of PE has been increasingly recognized in increasing insulin sensitivity, independent of body fat reduction by the training. 98 The protective effect of PE may be attributed to the anti-inflammatory effect of physical training mediated by a reduction in visceral fat and/or induction of an inflammatory environment, with elevation in IL-10 and interleukin-1 receptor antagonist (IL-1Ra) concentrations, and reduction in IL-6 and TNF- α . 99 As previously mentioned, visceral obesity is an important factor for the development of DM, which may be related to the increase in IL-6 and TNF- α . 100 Regular exercise can reduce baseline production of IL-6, by decreasing its plasma concentration at rest. 101 After acute moderate-intensity exercise, plasma IL-6 can increase in up to 100 times after a marathon (even though this is not adequate for obese individuals), but rapidly decreases compared with pre‑exercise values. 101 This cytokines also stimulates proliferation of β -cells, and increased IL-6 concentrations in response to PE can stimulate the release of glucagon-like peptide-1 (GLP-1), an important hormone that stimulates insulin secretion. 102,103 These evidences support a beneficial effect of IL-6 in the regulation of insulin secretion, which undoubtedly contributes to DM prevention. Regarding AMPK in DM2 and IR scenario, many studies have suggested that muscle contraction plays a central role, regardless of insulinemic status, where the activity of AMPK- α 2 in skeletal muscle in response to PE was similar to that in individuals without DM2, indicating a normal functioning of muscle AMPK in diabetics, which is particularly important in IR conditions. 104 In another study, an acute bout of aerobic exercise (one hour duration) at 75% of VO 2 max did not increase insulin sensitivity in obese diabetic subjects. Nevertheless, after seven sessions, there was an increment in glucose uptake rate, possibly stimulated by increased AMPK activity. It is of note that no difference was observed in the expression of proteins of insulin signaling pathways post‑exercise compared with baseline. 105 The action of Akt protein, previously mentioned as an important mediator of GLUT4 mobilization from GLUT4‑containing vesicles to the membrane, may be impaired by the mammalian homolog of Ddosophila tribbles TRB3, whose expression is increased in obesity. 106 However, PE seems to be able to reduce the expression of this protein TRB3. A study showed that acute exercise reduced TRB3 expression and reversed Akt phosphorylation in the skeletal muscle of obese animals. 107 On the other hand, one session of swimming reduced TRB3 levels in the hypothalamus of obese rats. 108 In a recent study by Wang et al., 109 the authors showed that aerobic training contributed to reduce inflammatory factors in mice with induced DM2. In addition to reducing body weight, there was a inhibition of TLR4 in hepatic cells of these animals, which, in turn, increased AMPK expression, ultimately contributing to the improvement of inflammation and IR. 109 Therefore, this pathway would also explain the importance of aerobic exercise in improving insulin sensitivity and glycemic control in DM2. These findings may lead to further studies, especially in humans, and open new horizons for the treatment of obesity and IR. PE can also exert beneficial effects on cardiovascular system by mechanisms including the increase in adiponectin. 110 Among its several functions, adiponectin can greatly suppress hepatic glucogenesis, stimulating the oxidation of fatty acids in the skeletal muscle and inhibiting the transcription of genes involved in glucose production. In insulin-responsive tissues, adiponectin improves the sensitivity to this hormone. 111,112 Hypoadiponectinemia, defined by plasma adiponectin levels lower than 4.0 µg/mL, was associated with decreased levels of circulating high-density lipoprotein, triglycerides and glucose, and increased risk of metabolic syndrome. Also, the risk for atherosclerosis was twice as high in individuals with low adiponectin levels. 113 The improvement in adiponectin levels has been associated with loss of subcutaneous and visceral adipose tissue induced by PE. 114 Studies have shown that aerobic PE alone 115 or combined 1143