Interleukin-6 depletion selectively improves hepatic insulin action in obesity.

Klover, Peter J.; Clementi, Alicia H.; Mooney, Robert A.

doi:10.1210/en.2004-1468

Cited by 273Adipokines, Inflammation, and Metabolic DiseasesCytokine Signaling Pathways and InteractionsRegulation of Appetite and Obesity

Interleukin-6 depletion selectively improves hepatic insulin action in obesity.

Klover, Peter J., Clementi, Alicia H., Mooney, Robert A.·2005·Endocrinology

DOI 10.1210/en.2004-1468

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Abstract

Obesity and insulin resistance are considered chronic inflammatory states, in part because circulating IL-6 is elevated. Exogenous IL-6 can induce hepatic insulin resistance in vitro and in vivo. The importance of endogenous IL-6, however, to insulin resistance of obesity is unresolved. To test the hypothesis that IL-6 contributes to the inflammation and insulin resistance of obesity, IL-6 was depleted in Lep(ob) mice by injection of IL-6-neutralizing antibody. In untreated Lep(ob) mice, signal transducer and activator of transcription-3 (STAT3) activation was increased compared with that in lean controls, consistent with an inflammatory state. With IL-6 depletion, activation of STAT3 in liver and adipose tissue and expression of haptoglobin were reduced. Expression of the IL-6-dependent, hepatic acute phase protein fibrinogen was also decreased. Using the hyperinsulinemic-euglycemic clamp technique, insulin-dependent suppression of endogenous glucose production was 89% in IL-6-depleted Lep(ob) mice, in contrast to only 32% in Lep(ob) controls, indicating a marked increase in hepatic insulin sensitivity. A significant change in glucose uptake in skeletal muscle after IL-6 neutralization was not observed. In a direct comparison of hepatic insulin signaling in Lep(ob) mice treated with anti-IL-6 vs. IgG-treated controls, insulin-dependent insulin receptor autophosphorylation and activation of Akt (pSer473) were increased by nearly 50% with IL-6 depletion. In adipose tissue, insulin receptor signaling showed no significant change despite major reductions in STAT3 phosphorylation and haptoglobin expression. In diet-induced obese mice, depletion of IL-6 improved insulin responsiveness in 2-h insulin tolerance tests. In conclusion, these results indicate that IL-6 plays an important and selective role in hepatic insulin resistance of obesity.

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In cultured hepatocytes, preadipocytes, and mature adipocytes, IL-6 directly impairs insulin action.
“In cultured hepatocytes (25)(26)(27)(28), preadipocytes, and mature adipocytes (29), IL-6 directly impairs insulin action.”
From Signaling Specificity of Interleukin-6 Action on Glucose and Lipid Metabolism in Skeletal Muscle (2006) · cites this paper as [25]

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Markan, K. R., Naber, M. C., Small, S. M., Peltekian, L., Kessler, R. L., & Potthoff, M. J. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.03.009 · Cited by 68 · see citing works

Authors: Klover, P. J., Clementi, A. H., & Mooney, R. A.
Affiliations: University of Rochester Medicine (US)
Corresponding author: Mooney, Robert A.
ORCID: Mooney, Robert A.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2005-08-01
Volume: 146
Issue: 8
Pages: 3417-3427
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2004-1468
OpenAlex: W1973416470
Cited by: 273
References: 46
Citations by year: 2026: 4 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 13 · 2020: 7 · 2019: 11 · 2018: 6 · 2017: 13 · 2016: 11 · 2015: 14 · 2014: 19 · 2013: 16 · 2012: 12
FWCI: 14.34
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (DK-38138, R01DK038138)
Topics: Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords: interleukin-6, hepatic insulin resistance, obesity, IL-6 neutralization, STAT3 activation, haptoglobin, fibrinogen, acute phase proteins, hepatic glucose production, insulin receptor signaling, Akt phosphorylation, adipose tissue, diet-induced obesity, inflammation
MeSH terms: Interleukin-6 Inhibitors, Adipose Tissue, Animals, Antibodies, DNA-Binding Proteins, Haptoglobins, Immunoglobulin G, Inflammation, Insulin, Liver, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Phosphorylation, Receptor, Insulin, Signal Transduction, Trans-Activators, Polymerase Chain Reaction, STAT3 Transcription Factor, Mice

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Interleukin-6 depletion selectively improves hepatic insulin action in obesity.

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