Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle

Ikeda, Shin‐ichi; Tamura, Yasuaki; Kakehi, Saori; Sanada, Hiromi; Kawamori, Ryuzo; Watada, Hirotaka

doi:10.1016/j.bbrc.2016.03.159

Cited by 66 publications

(53 citation statements)

References 27 publications

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“…IL-6 has previously been identified to be secreted form activated brown adipocytes (75). The role of IL-6 as a classic pro-inflammatory cytokine has to be reconsidered in light of recent data that IL-6 signaling can promote insulin sensitivity in skeletal muscle and adipose tissue of mice (76, 77). The importance for BAT as secretory organ has also been highlighted by a recent report identifying BAT as a source for circulating exosomal miRNAs, which function as negative regulators of translation.…”

Section: Bat As a Secretory Organmentioning

confidence: 99%

The significance of beige and brown fat in humans

Kiefer

2017

Endocrine Connections

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Promotion of brown adipose tissue (BAT) activity or browning of white adipose tissue has shown great potential as anti-obesity strategy in numerous preclinical models. The discovery of active BAT in humans and the recent advances in the understanding of human BAT biology and function have significantly propelled this field of research. Pharmacological stimulation of energy expenditure to counteract obesity has always been an intriguing therapeutic concept; with the identification of the specific molecular pathways of brown fat function, this idea has now become as realistic as ever. Two distinct strategies are currently being pursued; one is the activation of bone fide BAT, the other is the induction of BAT-like cells or beige adipocytes within white fat depots, a process called browning. Recent evidence suggests that both phenomena can occur in humans. Cold-induced promotion of BAT activity is strongly associated with enhanced thermogenesis and energy expenditure in humans and has beneficial effects on fat mass and glucose metabolism. Despite these encouraging results, a number of issues deserve additional attention including the distinct characteristics of human vs rodent BAT, the heterogeneity of human BAT depots or the identification of the adipocyte precursors that can give rise to thermogenic cells in human adipose tissue. In addition, many pharmaceutical compounds are being tested for their ability to promote a thermogenic program in human adipocytes. This review summarizes the current knowledge about the various cellular and molecular aspects of human BAT as well as the relevance for energy metabolism including its therapeutic potential for obesity.

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Section: Bat As a Secretory Organmentioning

confidence: 99%

The significance of beige and brown fat in humans

Kiefer

2017

Endocrine Connections

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“…The inflammatory response that follows an acute bout of exercise (reflected by increased IL‐6 levels that are produced by the contraction of skeletal muscle and the subsequent stimulation of a systemic increase in the concentration of anti‐inflammatory cytokines) is a mechanism that stimulates muscle regeneration and reduces low‐grade chronic inflammation and insulin resistance in adults, with in vitro studies reporting that IL‐10 inhibits the synthesis of chronic pro‐inflammatory mediators TNF‐α and IL‐1β . Furthermore, in the plantaris muscle of mice increased levels of IL‐6 post‐exercise increases the expression of glucose transporter‐4, which increases glucose uptake . These findings suggest that a rise in IL‐6 post‐exercise triggers an anti‐inflammatory response and enhances insulin sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Cytokine, glycemic, and insulinemic responses to an acute bout of games‐based activity in adolescents

Dring

Cooper

Morris

et al. 2019

Scandinavian Med Sci Sports

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An acute bout of endurance exercise in adults stimulates a same‐day anti‐inflammatory response which may affect low‐grade chronic inflammation and insulin resistance and benefit cardio‐metabolic health. The anti‐inflammatory responses to intermittent games‐based exercise and to exercise in young people beyond 2 hours post‐exercise are unknown. Thus, the purpose of the present study is to examine the anti‐inflammatory, glycemic and insulinemic response to games‐based activity in adolescents. Following ethical approval and familiarization, 39 adolescents (12.3 ± 0.7 years) completed an exercise (E) and rested (R) trial in a counterbalanced, randomized crossover design. Following a standardized breakfast, participants completed 1‐hour games‐based activity. Capillary blood samples were taken at baseline, immediately and 1 hour post‐exercise, and 30, 60 and 120 minutes following a standardized lunch. A final blood sample was taken the next morning. Data were analyzed using repeated measures ANOVA. IL‐6 concentration was higher on day one of the exercise trial (E:3.4 ± 0.4, R:2.7 ± 0.4 pg/mL; P = 0.006), as was the anti‐inflammatory IL‐6:TNF‐α ratio (E:5.53 ± 0.93, R:3.75 ± 0.45; P = 0.027). Levels of the anti‐inflammatory cytokine IL‐10 increased on day two of the exercise trial (E:2.11 ± 0.23, R:1.66 ± 0.16 pg/mL; P = 0.032). Insulin sensitivity was enhanced on the exercise trial with a reduction in iAUC following the standardized lunch (E:2310 ± 834, R:3122 ± 1443 mU/L × 120 minutes; P < 0.001). Games‐based activity stimulated an anti‐inflammatory response up to 24 hours post‐exercise and improved insulin sensitivity in response to a standardized meal in healthy adolescents. These novel findings suggest that games‐based activity is an ecologically valid mode of exercise to elicit beneficial effects on cardio‐metabolic risk factors in young people.

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“…Exogenous administration of low-dose IL-6 to treat DPN may be beneficial due to (1) increased insulin sensitivity in muscle (49), (2) decreased systemic inflammation (43, 44), (3) increased remyelination of axons (81–83), (4) increased nerve regeneration (96–98), (5) increased lipolysis (47, 48), and (6) decreased insulin secretion (34, 47). …”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, in this study as well as in several other studies performed in healthy volunteers (34, 35, 43, 47, 48) or T2D patients (34, 47), IL-6 infusion induced a significant decrease in circulating insulin, concomitantly with increases in lipolysis, without impacting glycemia or glucose uptake or release. Emerging preclinical research shows that IL-6 signaling following exercise increases glucose-transporter 4 (GLUT-4) expression resulting in increased insulin sensitivity (49). Altogether, these data suggest that, in addition to its activities on lipolysis, transient IL-6 might decrease insulin secretion and improve glycemia but not necessarily through a direct effect on glucose uptake but rather potentially through indirect mechanisms secondary to increased insulin sensitivity.…”

Section: Clinical Studies: Il-6 Administration To Mimic Exercisementioning

confidence: 99%

Low-Dose Pulsatile Interleukin-6 As a Treatment Option for Diabetic Peripheral Neuropathy

et al. 2017

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Diabetic peripheral neuropathy (DPN) remains one of the most common and serious complications of diabetes. Currently, pharmacological agents are limited to treating the pain associated with DPN, and do not address the underlying pathological mechanisms driving nerve damage, thus leaving a significant unmet medical need. Interestingly, research conducted using exercise as a treatment for DPN has revealed interleukin-6 (IL-6) signaling to be associated with many positive benefits such as enhanced blood flow and lipid metabolism, decreased chronic inflammation, and peripheral nerve fiber regeneration. IL-6, once known solely as a pro-inflammatory cytokine, is now understood to signal as a multifunctional cytokine, capable of eliciting both pro- and anti-inflammatory responses in a context-dependent fashion. IL-6 released from muscle in response to exercise signals as a myokine and as such has a unique kinetic profile, whereby levels are transiently elevated up to 100-fold and return to baseline levels within 4 h. Importantly, this kinetic profile is in stark contrast to long-term IL-6 elevation that is associated with pro-inflammatory states. Given exercise induces IL-6 myokine signaling, and exercise has been shown to elicit numerous beneficial effects for the treatment of DPN, a causal link has been suggested. Here, we discuss both the clinical and preclinical literature related to the application of IL-6 as a treatment strategy for DPN. In addition, we discuss how IL-6 may directly modulate Schwann and nerve cells to explore a mechanistic understanding of how this treatment elicits a neuroprotective and/or regenerative response. Collectively, studies suggest that IL-6, when administered in a low-dose pulsatile strategy to mimic the body’s natural response to exercise, may prove to be an effective treatment for the protection and/or restoration of peripheral nerve function in DPN. This review highlights the studies supporting this assertion and provides rationale for continued investigation of IL-6 for the treatment of DPN.

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Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle

Cited by 66 publications

References 27 publications

The significance of beige and brown fat in humans

The significance of beige and brown fat in humans

Cytokine, glycemic, and insulinemic responses to an acute bout of games‐based activity in adolescents

Low-Dose Pulsatile Interleukin-6 As a Treatment Option for Diabetic Peripheral Neuropathy

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