title: Muscle interleukin-6 and fasting-induced PDH regulation in mouse skeletal muscle.
abstract: Fasting prompts a metabolic shift in substrate utilization from carbohydrate to predominant fat oxidation in skeletal muscle, and pyruvate dehydrogenase (PDH) is seen as a controlling link between the competitive oxidation of carbohydrate and fat during metabolic challenges like fasting. Interleukin (IL)-6 has been proposed to be released from muscle with concomitant effects on both glucose and fat utilization. The aim was to test the hypothesis that muscle IL-6 has a regulatory impact on fasting-induced suppression of skeletal muscle PDH. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and floxed littermate controls (control) were either fed or fasted for 6 or 18 h. Lack of muscle IL-6 elevated the respiratory exchange ratio in the fed and early fasting state, but not with prolonged fasting. Activity of PDH in the active form (PDHa) was higher in fed and fasted IL-6 MKO than in control mice at 18 h, but not at 6 h, whereas lack of muscle IL-6 did not prevent downregulation of PDHa activity in skeletal muscle or changes in plasma and muscle substrate levels in response to 18 h of fasting. Phosphorylation of three of four sites on PDH-E1α increased with 18 h of fasting, but was lower in IL-6 MKO mice than in control. In addition, both PDK4 mRNA and protein increased with 6 and 18 h of fasting in both genotypes, but PDK4 protein was lower in IL-6 MKO than in control. In conclusion, skeletal muscle IL-6 seems to regulate whole body substrate utilization in the fed, but not fasted, state and influence skeletal muscle PDHa activity in a circadian manner. However, skeletal muscle IL-6 is not required for maintaining metabolic flexibility in response to fasting.
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Gudiksen
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Laerke
authors.initials: L
authors.lastname: Bertholdt
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mikkel Birkkjaer
authors.initials: MB
authors.lastname: Vingborg
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henriette Watson
authors.initials: HW
authors.lastname: Hansen
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stine
authors.initials: S
authors.lastname: Ringholm
authors.affiliation: Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark hpilegaard@bio.ku.dk.
authors.forename: Henriette
authors.initials: H
authors.lastname: Pilegaard
mesh_terms: D000818:Animals; D005215:Fasting / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015850:Interleukin-6; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; C577686:interleukin-6, mouse; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit; D017346:Protein Serine-Threonine Kinases
keywords: IL-6; PDH; fasting; metabolism; skeletal muscle; substrate utilization