IL-6 deficiency in mice neither impairs induction of metabolic genes in the liver nor affects blood glucose levels during fasting and moderately intense exercise

Fritsche, Louise; Hoene, Miriam; Lehmann, Rainer; Ellingsgaard, Helga; Hennige, Anita M.; Pohl, A; Häring, Hans‐Ulrich; Schleicher, Erwin; Weigert, Cora

doi:10.1007/s00125-010-1754-4

Cited by 32 publications

(29 citation statements)

References 49 publications

(55 reference statements)

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“…Our results are in accordance with the findings by [36] that IL-6 is not necessary for glucose production during non-exhaustive exercise. It was also recently reported, in contrast to previous observations, that IL-6 release in humans during exercise was not directly correlated with the release or uptake of exogenous substrate, nor to muscle glycogen utilization [37].…”

Section: Discussionsupporting

confidence: 93%

Running Performance at High Running Velocities Is Impaired but V′O2max and Peripheral Endothelial Function Are Preserved in IL-6−/− Mice

et al. 2014

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It has been reported that IL-6 knockout mice (IL-6−/−) possess lower endurance capacity than wild type mice (WT), however the underlying mechanism is poorly understood. The aim of the present work was to examine whether reduced endurance running capacity in IL-6−/− mice is linked to impaired maximal oxygen uptake (V′O2max), decreased glucose tolerance, endothelial dysfunction or other mechanisms. Maximal running velocity during incremental running to exhaustion was significantly lower in IL-6−/− mice than in WT mice (13.00±0.97 m.min−1 vs. 16.89±1.15 m.min−1, P<0.02, respectively). Moreover, the time to exhaustion during running at 12 m.min−1 in IL-6−/− mice was significantly shorter (P<0.05) than in WT mice. V′O2max in IL-6−/− (n = 20) amounting to 108.3±2.8 ml.kg−1.min−1 was similar as in WT mice (n = 22) amounting to 113.0±1.8 ml.kg−1.min−1, (P = 0.16). No difference in maximal COX activity between the IL-6−/− and WT mice in m. soleus and m. gastrocnemius was found. Moreover, no impairment of peripheral endothelial function or glucose tolerance was found in IL-6−/− mice. Surprisingly, plasma lactate concentration during running at 8 m.min−1 as well at maximal running velocity in IL-6−/− mice was significantly lower (P<0.01) than in WT mice. Interestingly, IL-6−/− mice displayed important adaptive mechanisms including significantly lower oxygen cost of running at a given speed accompanied by lower expression of sarcoplasmic reticulum Ca2+-ATPase and lower plasma lactate concentrations during running at submaximal and maximal running velocities. In conclusion, impaired endurance running capacity in IL-6−/− mice could not be explained by reduced V′O2max, endothelial dysfunction or impaired muscle oxidative capacity. Therefore, our results indicate that IL-6 cannot be regarded as a major regulator of exercise capacity but rather as a modulator of endurance performance. Furthermore, we identified important compensatory mechanism limiting reduced exercise performance in IL-6−/− mice.

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Section: Discussionsupporting

confidence: 93%

Running Performance at High Running Velocities Is Impaired but V′O2max and Peripheral Endothelial Function Are Preserved in IL-6−/− Mice

et al. 2014

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“…The role of IL-6 in glucose metabolism and metabolic homeostasis is complex. As a result, genetic models of Il-6 deletion have yielded conflicting metabolic phenotypes (50)(51)(52)(53). Our current results demonstrated that IL-13 is a physiological signal that activates hepatic STAT3 to suppress glucose production.…”

Section: Methodsmentioning

confidence: 71%

Direct control of hepatic glucose production by interleukin-13 in mice

et al. 2012

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Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13 -/-) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13 -/-mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.

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“…However, this effect seems to be related to another as yet unidentified factor released during contraction since IL-6 infusion alone is not able to increase hepatic glucose production in resting individuals [24]. Interestingly, IL-6-deficient mice display a similar level of blood glucose as wild-type controls after nonexhaustive exercise, suggesting that, at least in mice, IL-6 is not necessary for hepatic glucose production during exercise [25]. Furthermore, animal studies have shown that IL-6 impairs the ability of insulin to suppress hepatic glucose production [26,27], whereas this is not the case in humans [19].…”

Section: Myokines and Metabolic Regulationmentioning

confidence: 94%

Myokines in insulin resistance and type 2 diabetes

et al. 2014

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Skeletal muscle represents the largest organ of the body in non-obese individuals and is now considered to be an active endocrine organ releasing a host of so-called myokines. These myokines are part of a complex network that mediates communication between muscle, the liver, adipose tissue, the brain and other organs. Recent data suggest that myokines regulated by muscle contraction may play a key role in mediating the health-promoting effects of regular physical activity. Although hundreds of myokines have recently been described in proteomic studies, we currently have a rather limited knowledge of the specific role these myokines play in the prevention of insulin resistance, inflammation and associated metabolic dysfunction. Several myokines are known to have both local and endocrine functions, but in many cases the contribution of physical activity to the systemic level of these molecules remains as yet unexplored. Very recently, novel myokines such as irisin, which is thought to induce a white to brown shift in adipocytes, have gained considerable interest as potential therapeutic targets. In this review, we summarise the most recent findings on the role of myokines in the regulation of substrate metabolism and insulin sensitivity. We further explore the role of myokines in the regulation of inflammation and provide a critical assessment of irisin and other myokines regarding their potential as therapeutic targets.

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IL-6 deficiency in mice neither impairs induction of metabolic genes in the liver nor affects blood glucose levels during fasting and moderately intense exercise

Cited by 32 publications

References 49 publications

Running Performance at High Running Velocities Is Impaired but V′O2max and Peripheral Endothelial Function Are Preserved in IL-6−/− Mice

Running Performance at High Running Velocities Is Impaired but V′O2max and Peripheral Endothelial Function Are Preserved in IL-6−/− Mice

Direct control of hepatic glucose production by interleukin-13 in mice

Myokines in insulin resistance and type 2 diabetes

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