Impact of skeletal muscle IL-6 on regulation of liver and adipose tissue metabolism during fasting
The liver and adipose tissue are important tissues in whole-body metabolic regulation during fasting. Interleukin 6 (IL-6) is a cytokine shown to be secreted from contracting muscle in humans and suggested to signal to the liver and adipose tissue. Furthermore, skeletal muscle IL-6 has been proposed to play a role during fasting. Therefore the aim of the present study was to investigate the role of skeletal muscle IL-6 in the regulation of substrate production in the liver and adipose tissue during fasting. Male skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and littermate floxed (control) mice fasted for 6 or 18 h (6 h fasting or 18 h fasting) with corresponding fed control groups (6 h fed or 18 h fed) and liver and adipose tissue were quickly obtained. Plasma β-hydroxybutyrate increased and hepatic glucose, lactate and glycogen decreased with fasting. In addition, fasting increased phosphoenolpyruvate carboxykinase protein and phosphorylation of pyruvate dehydrogenase (PDH) in the liver as well as hormone-sensitive lipase (HSL)Ser660 and HSLSer563 phosphorylation, PDH phosphorylation, adipose triglyceride lipase phosphorylation and perilipin phosphorylation and protein content in adipose tissue without any effect of lack of skeletal muscle IL-6. In conclusion, fasting induced regulation of enzymes in adipose tissue lipolysis and glyceroneogenesis as well as regulation of hepatic gluconeogenic capacity and hepatic substrate utilization in mice. However, skeletal muscle IL-6 was not required for these fasting-induced effects, but had minor effects on markers of lipolysis and glyceroneogenesis in adipose tissue as well as markers of hepatic gluconeogenesis in the fed state.
KeywordsSkeletal muscle IL-6 Fasting Adipose tissue lipolysis Hepatic glucose production Substrate regulation
The authors would like to thank Stine Ringholm for technical assistance and Professor Grahame Hardie (University of Dundee) for providing antibodies as well as Professor Juan Hidalgo (Universidad de Autonoma de Barcelona) for initially providing floxed IL-6 mice to start breeding.
This study was funded by Danish Council for Independent Research, Natural Sciences (4004-00134) and The Danish Diabetes Academy (1105701001).
Compliance with ethical standards
The authors have nothing to disclose.
- 1.Banzet S, Koulmann N, Simler N, Sanchez H, Chapot R, Serrurier B, Peinnequin A, Bigard X (2009) Control of gluconeogenic genes during intense/prolonged exercise: hormone-independent effect of muscle-derived IL-6 on hepatic tissue and PEPCK mRNA. J Appl Physiol (1985) 107:1830–1839CrossRefGoogle Scholar
- 3.Bertholdt L, Gudiksen A, Stankiewicz T, Villesen I, Tybirk J, van HG, Bangsbo J, Plomgaard P, Pilegaard H (2017b) Impact of training state on fasting-induced regulation of adipose tissue metabolism in humans. J Appl Physiol (1985)Google Scholar
- 6.Cadoudal T, Blouin JM, Collinet M, Fouque F, Tan GD, Loizon E, Beale EG, Frayn KN, Karpe F, Vidal H, Benelli C, Forest C (2007) Acute and selective regulation of glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase in adipose tissue by thiazolidinediones in type 2 diabetes. Diabetologia 50:666–675CrossRefPubMedCentralGoogle Scholar
- 9.Dohm GL, Kasperek GJ, Barakat HA (1985) Time course of changes in gluconeogenic enzyme activities during exercise and recovery. Am J Phys 249:E6–E11Google Scholar
- 12.Feldman D, Hirst M (1978) Glucocorticoids and regulation of phosphoenolpyruvate carboxykinase activity in rat brown adipose tissue. Am J Phys 235:E197–E202Google Scholar
- 14.Frasson D, Boschini RP, Chaves VE, dos Santos ME, Paula GS, Valentim RR, Garofalo MA, Navegantes LC, Migliorini RH, Kettelhut IC (2012) The sympathetic nervous system regulates the three glycerol-3P generation pathways in white adipose tissue of fasted, diabetic and high-protein diet-fed rats. Metabolism 61:1473–1485CrossRefPubMedCentralGoogle Scholar
- 18.Haase TN, Ringholm S, Leick L, Bienso RS, Kiilerich K, Johansen S, Nielsen MM, Wojtaszewski JF, Hidalgo J, Pedersen PA, Pilegaard H (2011) Role of PGC-1alpha in exercise and fasting-induced adaptations in mouse liver. Am J Physiol Regul Integr Comp Physiol 301:R1501–R1509CrossRefPubMedCentralGoogle Scholar
- 19.Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R (2006) Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312:734–737CrossRefPubMedCentralGoogle Scholar
- 33.Lowry OH, Passonneau JV (1972) A flexible system of enzymatic analysis. Academic Press Ref type: GenericGoogle Scholar
- 36.Pagnon J, Matzaris M, Stark R, Meex RC, Macaulay SL, Brown W, O'Brien PE, Tiganis T, Watt MJ (2012) Identification and functional characterization of protein kinase A phosphorylation sites in the major lipolytic protein, adipose triglyceride lipase. Endocrinology 153:4278–4289CrossRefPubMedCentralGoogle Scholar
- 44.Wueest S, Item F, Boyle CN, Jirkof P, Cesarovic N, Ellingsgaard H, Boni-Schnetzler M, Timper K, Arras M, Donath MY, Lutz TA, Schoenle EJ, Konrad D (2014) Interleukin-6 contributes to early fasting-induced free fatty acid mobilization in mice. Am J Physiol Regul Integr Comp Physiol 306:R861–R867CrossRefPubMedCentralGoogle Scholar