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Cited by 18Cytokine Signaling Pathways and InteractionsAdipokines, Inflammation, and Metabolic DiseasesLiver physiology and pathology

Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma

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Mittenbühler, Melanie J., Sprenger, Hans-Georg, Gruber, Sabine, Wunderlich, Claudia M., Kern, Lara, Brüning, Jens C., Wunderlich, F. Thomas·2018·Molecular Metabolism
DOI 10.1016/j.molmet.2018.08.010PMC PMC6197506
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Abstract

OBJECTIVE: The current obesity pandemic represents a major health burden, given that it predisposes to the development of numerous obesity-associated disorders. The obesity-derived adipokines not only impair systemic insulin action but also increase the incidence of hepatocellular carcinoma (HCC), a highly prevalent cancer with poor prognosis. Thus, worldwide incidences of HCC are expected to further increase, and defining the molecular as well as cellular mechanisms will allow for establishing new potential treatment options. The adipose tissue of obese individuals increases circulating leptin and interleukin-6 (IL-6) levels, which both share similar signaling capacities such as Signal Transducer and Activator of Transcription 3 (STAT3) and Phosphoinositide 3-kinase (PI3K)/Akt activation. While mouse models with deficient IL-6 signaling show an ameliorated but not absent Diethylnitrosamine (DEN)-induced HCC development, the morbid obesity in mice with mutant leptin signaling complicates the dissection of hepatic leptin receptor (LEPR) and IL-6 signaling in HCC development. Here we have investigated the function of compensating hepatic LEPR expression in HCC development of IL-6Rα-deficient mice. METHODS: We generated and characterized a mouse model of hepatic LEPR deficiency that was intercrossed with IL-6Rα-deficient mice. Cohorts of single and double knockout mice were subjected to the DEN-HCC model to ascertain liver cancer development and characterize metabolic alterations. RESULTS: /IL-6Rα knock out mice, whereas metabolism remained largely unaltered between the genotypes. CONCLUSIONS: Our findings reveal a compensatory role for hepatic LEPR in HCC development of IL-6Rα-deficient mice and suggest hepatocyte-specific leptin signaling as promoter of HCC under obese conditions.

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  • IL-6 or gp130 knockout mice develop significantly fewer tumors in DEN-induced HCC model and have prolonged survival.

    “Indeed, IL-6 or gp130 knockout mice developed significantly less tumors in the diethylnitrosamine (DEN)-induced HCC model and prolonged survival [63, 64]”

    From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [63]

    The Results section reports reduced DEN-induced tumor burden in IL-6Rα-deficient mice. It does not establish the same result for IL-6 or gp130 knockout mice, and the study ended at eight months rather than measuring prolonged survival. (LLM, conf=0.88)

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Authors
Mittenbühler, M. J., Sprenger, H.-G., Gruber, S., Wunderlich, C. M., Kern, L., Brüning, J. C., & Wunderlich, F. T.
Affiliations
  • Max Planck Institute for Metabolism Research (DE)
  • Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
Corresponding author
Wunderlich, F. Thomas
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2018-11
Volume
17
Pages
122-133
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2018.08.010
PMC
PMC6197506
OpenAlex
W2890154310
Cited by
18
References
7
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 1
FWCI
0.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Metabolism (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
German Cancer Aid
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
leptin receptor, IL-6 receptor alpha, hepatocellular carcinoma, diethylnitrosamine, obesity, adipokines, compensatory signaling, STAT3, PI3K/Akt signaling, liver cancer development, metabolic changes
MeSH terms
Animals, Diethylnitrosamine, Disease Models, Animal, Female, Liver Neoplasms, Experimental, Male, Mice, Inbred C57BL, Phosphorylation, Signal Transduction, Gene Expression, Mice, Knockout, Phosphatidylinositol 3-Kinases, Leptin, Hepatocytes, Cell Proliferation, Lipid Metabolism, STAT3 Transcription Factor, Mice, Interleukin-6 Receptor alpha Subunit, Receptors, Leptin, Diet, High-Fat

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