Skeletal muscle IL-6 and regulation of liver metabolism during high-fat diet and exercise training

Altres ajuts: The study was supported by grants from the Lundbeck Foundation, The Danish Research Foundation, The Danish Council for Independent Research in the Natural Sciences, and The Augustinus Foundation. Centre of Inflammation and Metabolism (CIM) is supported by a grant from the Danish National Research Foundation (#02-512-55).Interleukin ()-6 is released from skeletal muscle (SkM) during exercise and has been shown to affect hepatic metabolism. It is, however, unknown whether SkM -6 is involved in the regulation of exercise training-induced counteraction of changes in carbohydrate and lipid metabolism in the liver in response to high-fat diet () feeding. Male SkM-specific -6 () and Floxed mice were subjected to Chow diet, or combined with exercise training ( ExTr) for 16 weeks. Hepatic phosphoenolpyruvate carboxykinase () protein content decreased with both and ExTr in Floxed mice, but increased in -6 mice on . In addition, the intrahepatic glucose concentration was in -6 mice higher in than chow. Within ExTr mice, hepatic glucose-6-phosphatase (G6Pase) 36 a protein content was higher in -6 than Floxed mice. Hepatic pyruvate dehydrogenase kinase () 4 and 2 protein content was in Floxed mice lower in ExTr than Chow. In addition, hepatic 1-phosphorylation was higher and 1 protein lower in . Together this suggests that SkM -6 regulates hepatic glucose metabolism, but does not seem to be of major importance for the regulation of oxidative capacity or lipogenesis in liver during or combined with exercise training

Skeletal muscle interleukin-6 regulates metabolic factors in iWAT during HFD and exercise training

To investigate the role of skeletal muscle (SkM) interleukin (IL)-6 in the regulation of adipose tissue metabolism. Muscle-specific IL-6 knockout (IL-6 MKO) and IL-6 loxP/loxP (Floxed) mice were subjected to standard rodent diet (Chow), high-fat diet (HFD), or HFD in combination with exercise training (HFD ExTr) for 16 weeks. Total fat mass increased (P < 0.05) in both genotypes with HFD. However, HFD IL-6 MKO mice had lower (P < 0.05) inguinal adipose tissue (iWAT) mass than HFD Floxed mice. Accordingly, iWAT glucose transporter 4 (GLUT4) protein content, 5'AMP activated protein kinase (AMPK) Thr172 phosphorylation, and fatty acid synthase (FAS) mRNA content were lower (P < 0.05) in IL-6 MKO than Floxed mice on Chow. In addition, iWAT AMPK Thr172 and hormone-sensitive lipase (HSL) Ser565 phosphorylation as well as perilipin protein content was higher (P < 0.05) in HFD IL-6 MKO than HFD Floxed mice, and pyruvate dehydrogenase E1α (PDH-E1α) protein content was higher (P < 0.05) in HFD ExTr IL-6 MKO than HFD ExTr Floxed mice. These findings indicate that SkM IL-6 affects iWAT mass through regulation of glucose uptake capacity as well as lipogenic and lipolytic factors

Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise.

Pyruvate dehydrogenase (PDH) plays a key role in the regulation of skeletal muscle substrate utilization. IL-6 is produced in skeletal muscle during exercise in a duration dependent manner and has been reported to increase whole body fatty acid oxidation, muscle glucose uptake and decrease PDHa activity in skeletal muscle of fed mice. The aim of the present study was to examine whether muscle IL-6 contributes to exercise-induced PDH regulation in skeletal muscle. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and floxed littermate controls (control) completed a single bout of treadmill exercise for 10, 60 or 120 min, with rested mice of each genotype serving as basal controls. The respiratory exchange ratio (RER) was overall higher (P<0.05) in IL-6 MKO than control mice during the 120 min of treadmill exercise, while RER decreased during exercise independent of genotype. AMPK and ACC phosphorylation also increased with exercise independent of genotype. PDHa activity was in control mice higher (P<0.05) at 10 and 60 min of exercise than at rest but remained unchanged in IL-6 MKO mice. In addition, PDHa activity was higher (P<0.05) in IL-6 MKO than control mice at rest and 60 min of exercise. Neither PDH phosphorylation nor acetylation could explain the genotype differences in PDHa activity. Together, this provides evidence that skeletal muscle IL-6 contributes to the regulation of PDH at rest and during prolonged exercise and suggests that muscle IL-6 normally dampens carbohydrate utilization during prolonged exercise via effects on PDH

Skeletal muscle interleukin-6 regulates metabolic factors in i during and exercise training

To investigate the role of skeletal muscle (SkM) interleukin (IL)-6 in the regulation of adipose tissue metabolism. Muscle-specific IL-6 knockout (IL-6 MKO) and IL-6 loxP/loxP (Floxed) mice were subjected to standard rodent diet (Chow), high-fat diet (HFD), or HFD in combination with exercise training (HFD ExTr) for 16 weeks. Total fat mass increased (P < 0.05) in both genotypes with HFD. However, HFD IL-6 MKO mice had lower (P < 0.05) inguinal adipose tissue (iWAT) mass than HFD Floxed mice. Accordingly, iWAT glucose transporter 4 (GLUT4) protein content, 5'AMP activated protein kinase (AMPK) Thr172 phosphorylation, and fatty acid synthase (FAS) mRNA content were lower (P < 0.05) in IL-6 MKO than Floxed mice on Chow. In addition, iWAT AMPK Thr172 and hormone-sensitive lipase (HSL) Ser565 phosphorylation as well as perilipin protein content was higher (P < 0.05) in HFD IL-6 MKO than HFD Floxed mice, and pyruvate dehydrogenase E1α (PDH-E1α) protein content was higher (P < 0.05) in HFD ExTr IL-6 MKO than HFD ExTr Floxed mice. These findings indicate that SkM IL-6 affects iWAT mass through regulation of glucose uptake capacity as well as lipogenic and lipolytic factors

Skeletal muscle -6 and regulation of liver metabolism during high-fat diet and exercise training

Altres ajuts: The study was supported by grants from the Lundbeck Foundation, The Danish Research Foundation, The Danish Council for Independent Research in the Natural Sciences, and The Augustinus Foundation. Centre of Inflammation and Metabolism (CIM) is supported by a grant from the Danish National Research Foundation (#02-512-55).Interleukin ()-6 is released from skeletal muscle (SkM) during exercise and has been shown to affect hepatic metabolism. It is, however, unknown whether SkM -6 is involved in the regulation of exercise training-induced counteraction of changes in carbohydrate and lipid metabolism in the liver in response to high-fat diet () feeding. Male SkM-specific -6 () and Floxed mice were subjected to Chow diet, or combined with exercise training ( ExTr) for 16 weeks. Hepatic phosphoenolpyruvate carboxykinase () protein content decreased with both and ExTr in Floxed mice, but increased in -6 mice on . In addition, the intrahepatic glucose concentration was in -6 mice higher in than chow. Within ExTr mice, hepatic glucose-6-phosphatase (G6Pase) 36 a protein content was higher in -6 than Floxed mice. Hepatic pyruvate dehydrogenase kinase () 4 and 2 protein content was in Floxed mice lower in ExTr than Chow. In addition, hepatic 1-phosphorylation was higher and 1 protein lower in . Together this suggests that SkM -6 regulates hepatic glucose metabolism, but does not seem to be of major importance for the regulation of oxidative capacity or lipogenesis in liver during or combined with exercise training

Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise - Fig 3

<p><b>A)</b> AMP-activated protein kinase (AMPK) Thr172 phosphorylation and <b>B)</b> Acetyl-CoA carboxylase 2 (ACC2) phosphorylation in skeletal muscle from skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed controls (Control) mice at rest and after 10, 60 or 120 min of exercise. Values are given as mean ± SE; n = 9–10. Phosphorylation levels are given in arbitrary units (AU). *: significantly different from rest within given genotype, P<0.05. #: significantly different from control within given time point, P<0.05. (*): Tendency to be significantly different from rest within given genotype, 0.05</p

Skeletal muscle glucose, G-6-P, glycogen, lactate, and acetyl CoA content.

<p>Skeletal muscle glucose, glucose -6 phosphate (G-6-P), glycogen, lactate and acetyl CoA in skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed controls (Control) mice at rest and after 10, 60 or 120 min of exercise. Values are given as mean ± SE; n = 9–10.</p

Respiratory Exchange Ratio (RER) in skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed controls (Control) during 120 min of metabolic treadmill exercise.

<p>Values are given as mean ± SE for every 10 minutes of continuous measurements; n = 5–7. *: significantly different from 10 min within given genotype, P<0.05. #: significantly different from control within given time point, P<0.05.</p

PDHa activity in skeletal muscle from skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate floxed controls (Control) at rest and after 10, 60 or 120 min of exercise.

<p>Values are given as mean ± SE; n = 10. *: significantly different from rest within given genotype, P<0.05. #: significantly different from control within given time point, P<0.05.</p