Control of gluconeogenic genes during intense/prolonged exercise: hormone-independent effect of muscle-derived IL-6 on hepatic tissue and PEPCK mRNA

• Published in: Journal of applied physiology (1985) Vol. 107; no. 6; pp. 1830 - 1839
• Main Authors: Banzet, Sebastien, Koulmann, Nathalie, Simler, Nadine, Sanchez, Herve, Chapot, Rachel, Serrurier, Bernard, Peinnequin, Andre, Bigard, Xavier
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Am Physiological Soc 01.12.2009; American Physiological Society
• Subjects: Analysis of Variance; Animals; Biological and medical sciences; Blood Glucose - metabolism; Blotting, Western; Cytokines; Enzyme-Linked Immunosorbent Assay; Exercise; Female; Fundamental and applied biological sciences. Psychology; Gluconeogenesis - drug effects; Gluconeogenesis - genetics; Glucose; Glucose-6-Phosphatase - genetics; Glucose-6-Phosphatase - metabolism; Glycogen - metabolism; Human health and pathology; Interleukin-6 - administration & dosage; Interleukin-6 - metabolism; Life Sciences; Liver; Liver - drug effects; Liver - metabolism; Muscle, Skeletal - metabolism; Musculoskeletal system; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphoenolpyruvate Carboxykinase (GTP) - genetics; Phosphoenolpyruvate Carboxykinase (GTP) - metabolism; Physical Exertion - physiology; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Rodents; Time Factors; Tissues and Organs; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation - physiology; Physical exercise; phosphoenolpyruvate-carboxykinase; Cytokine; myokine; Glucose; Striated muscle; Interleukin 6; Tissue; Vertebrata; hepatic glucose production; Mammalia; Gene; Prolonged
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.00739.2009

Department of Human Factors, Military Health Service Research Center (Centre de Recherches du Service de Santé des Armées), La Tronche, France Submitted 10 July 2009 ; accepted in final form 17 October 2009 Prolonged intense exercise is challenging for the liver to maintain plasma glucose levels. Hormonal changes cannot fully account for exercise-induced hepatic glucose production (HGP). Contracting skeletal muscles release interleukin-6 (IL-6), a cytokine able to increase endogenous glucose production during exercise. However, whether this is attributable to a direct effect of IL-6 on liver remains unknown. Here, we studied hepatic glycogen, gluconeogenic genes, and IL-6 signaling in response to one bout of exhaustive running exercise in rats. To determine whether IL-6 can modulate gluconeogenic gene mRNA independently of exercise, we injected resting rats with recombinant IL-6. Exhaustive exercise resulted in a profound decrease in liver glycogen and an increase in gluconeogenic gene mRNA levels, phosphoenolpyruvate-carboxykinase (PEPCK), glucose-6-phosphatase (G6P), and peroxisome proliferator-activated receptor- coactivator-1 (PGC-1 ), suggesting a key role for gluconeogenesis in hepatic glucose production. This was associated to an active IL-6 signaling in liver tissue, as shown by signal transducer and activator of transcription and CAAT/enhancer binding protein-β phosphorylation and IL-6-responsive gene mRNA levels at the end of exercise. Recombinant IL-6 injection resulted in an increase in IL-6-responsive gene mRNA levels in the liver. We found a dose-dependent increase in PEPCK gene mRNA strongly correlated with IL-6-induced gene mRNA levels. No changes in G6P and PGC-1 mRNA levels were found. Taken together, our results suggest that, during very demanding exercise, muscle-derived IL-6 could help increase HGP by directly upregulating PEPCK mRNA abundance. hepatic glucose production; myokine; phosphoenolpyruvate-carboxykinase Address for reprint requests and other correspondence: S. Banzet, CRSSA, Dept. of Human Factors, BP 87, 38702 La Tronche Cedex, France (e-mail: sbanzet{at}crssa.net ).