Control of gluconeogenic genes during intense/prolonged exercise: hormone-independent effect of muscle-derived IL-6 on hepatic tissue and PEPCK mRNA
Open accessAbstract
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-gamma coactivator-1alpha (PGC-1alpha), 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-beta 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-1alpha 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.
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Gluconeogenesis is normally not engaged in positive energy balance states, with the exception of forced exercise.
“Gluconeogenesis is normally not engaged in positive energy balance states, with the exception of forced exercise (Banzet et al., 2009).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Banzet et al., 2009
Other studies demonstrate STAT3 regulation of the same gluconeogenic genes such as Pck1 and G6pc and a role for IL6 in exercise-mediated hepatic gluconeogenesis.
“While IL6 does not appear to increase gluconeogenesis at rest (Steensberg et al., 2003), our studies resonate well with other studies demonstrating STAT3 regulation of the same gluconeogenic genes such as Pck1 and G6pc and by studies demonstrating a role for IL6 in exercise-mediated hepatic gluconeogenesis (Banzet et al., 2009).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Banzet et al., 2009
In forced exercise, IL6 is derived from myocytes and induces hepatic gluconeogenesis.
“In this setting, IL6 is derived from myocytes and induces hepatic gluconeogenesis.”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Banzet et al., 2009
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“increased the hepatic phosphoenolpyruvate carboxykinase (PEPCK) messenger RNA (mRNA), a key enzyme of gluconeogenesis.(7) However, others studies showed that IL6 prevented the increase in PEPCK mRNA during the initial fasting phase(8) and attenuated the expression of PEPCK induced by glucagon(9) and dexamethasone/cAMP.”
BackgroundTHE ROLE OF MYOKINES INTERSTITIAL INTERACTION AND REGULATION OF METABOLISM: A REVIEW OF LITERATURE
Тамерланович, Ц. Т., White, Z. E., & Rozhinskaya, L. Y. (2016) · Osteoporosis and Bone Diseases · doi:10.14341/osteo2016128-34 · Cited by 7 · see citing works
Tardo‐Dino, P., Taverny, C., Siracusa, J., Bourdon, S., Baugé, S., Koulmann, N., & Malgoyre, A. (2021) · Physiological Reports · doi:10.14814/phy2.14686 · Cited by 4 · see citing works
“…measurement of NADH production (λ = 340 nm) in the presence of hexokinase (H4502 Sigma) and glucose6- phosphate dehydrogenase (G6378 Sigma), according to the method of Bergmeyer (Bergmeyer & Grassl, 1983; Passonneau & Lauderdale, 1974) and as previously described in (Banzet et al., 2009).”
MethodIL-6 in non-alcoholic fatty liver disease – good, evil or both?
Buechler, C. (2012) · Endocrinology & Metabolic Syndrome · doi:10.4172/2161-1017.1000e101 · Cited by 3 · see citing works
“Muscle derived IL-6 is suggested to enhance hepatic glucose release to provide additional energy [18-20].”
BackgroundNutrition, santé et performance du sportif d’endurance
Rousseau, A. (2022) · Cahiers de Nutrition et de Diététique · doi:10.1016/j.cnd.2021.11.004 · Cited by 2 · see citing works
Farzanegi, P., Abdi, M., Ghanbari–Niaki, A., Fathi, R., & Hedayati, M. (2012) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 2 · see citing works
Metabolic and immune/inflammatory alterations induced by a triathlon under extreme conditions
Momesso, C. M., do Amaral, J. B., Rossi, M. N., Vieria, R. P., Abad, C. C. C., & Bachi, A. L. L. (2022) · Frontiers in Sports and Active Living · doi:10.3389/fspor.2022.915343 · Cited by 2 · see citing works
The Effect of Manipulating the IL-6 Response to Exercise on Biomarkers and Exercise Performance
Walshe, I. H. (2012) · Northumbria Research Link (Northumbria University)
Opheim, M. N. (2010) · VTechWorks (Virginia Tech)
Schroer, A. B. (2013) · JMU Scholoraly Commons (James Madison University)
Faculty Opinions recommendation of Origin and Function of Stress-Induced IL-6 in Murine Models.
Lynch, L. (2021) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.738227474.793583818
Dahleh, M. M. M., Araújo, S. M., Bortolotto, V. C., Pinheiro, F. C., Machado, F. R., Meichtry, L. B., Musachio, E. A. S., Guerra, G. P., & Prigol, M. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4176845
Muscle-Liver Crosstalk and Sarcopenia
Pérez-Torres, D., & Canas-Pérez, I. (2025) · Springer eBooks · doi:10.1007/978-3-032-01024-7_19
- Authors
- Banzet, S., Koulmann, N., Simler, N., Sanchez, H., Chapot, R., Serrurier, B., Peinnequin, A., & Bigard, X.
- Affiliations
- Service de Santé des Armées (FR)
- Corresponding author
- Banzet, Sébastien
- Venue
- Journal of Applied Physiology
- Publisher
- American Physiological Society
- Published
- 2009-12
- Volume
- 107
- Issue
- 6
- Pages
- 1830-1839
- ISSN
- 0161-7567 (ISSN-L)
- 8750-7587
- 1522-1601
- OpenAlex
- W2027721904
- Cited by
- 42
- References
- 48
- Citations by year
- 2025: 2 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 7
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- green
- ssa.hal.science
- Licence
- other-oa
- Locations
- Journal of Applied Physiology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- interleukin-6, hepatic glucose production, gluconeogenesis, phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, PGC-1α, liver glycogen, physical activity, IL-6 signaling, STAT3, C/EBPβ, exhaustive running, plasma glucose
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Analysis of Variance, Animals, Blood Glucose, Enzyme-Linked Immunosorbent Assay, Physical Exertion, Female, Gluconeogenesis, Glucose-6-Phosphatase, Glycogen, Liver, Phosphoenolpyruvate Carboxykinase (GTP), RNA, Messenger, Time Factors, Transcription Factors, Blotting, Western, Transcriptional Activation, Interleukin-6, RNA-Binding Proteins, Rats, Wistar, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Rats
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