Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF Expression
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Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.
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IL-6-STAT3 signaling in adipocytes is involved in adipocyte-induced EMT in breast cancer cells and obesity-promoted HCC.
“IL-6–STAT3 signaling in adipocytes is known to be involved in adipocyte-induced EMT in breast cancer cells (23) and obesity-promoted HCC (258).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [258]
The Results section, “Enhanced IL-6 production is required for obesity-induced tumor promotion,” reports that IL-6 deficiency prevented STAT3 activation in obese mouse livers and HCCs and largely eliminated obesity-associated tumor promotion. The Discussion places IL-6–STAT3 signaling in hepatocytes, not adipocytes; it does not establish that signaling within adipocytes promotes HCC. The breast-cancer portion is attached to a different citation and is not assessed here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredElevated conjugated bile acids were also observed in other mouse liver cancer models, including hydrodynamic tail vein injection of Δ90-β-catenin plus hMET and DEN plus high-fat diet.
“Similarly, elevated conjugated BAs were observed in other mouse models of liver cancer such as hydrodynamic tail vein injection of constitutively active β-catenin (Δ90-β-catenin) plus human hepatocyte growth factor receptor (hMET) (17) and diethylnitrosamine (DEN) plus high-fat diet (HFD) (fig. S2C) (18).”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [18]
IL-6 appears to be an essential factor common to the induction of HCC by a variety of stimuli, including chemical, obesity and FGF19.
“Notably, IL-6 appears to be an essential factor common to the induction of HCC by a variety of stimuli, including chemical61, obesity62 and FGF19.”
From Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis (2017) · cites this paper as [62]
Development of pristane or mineral oil-induced plasmacytoma and obesity-related hepatocellular carcinoma are dependent on IL-6.
“Taken together with the fact that the development of pristane or mineral oil-induced plasmacytoma and obesity-related hepatocellular carcinoma (HCC), both of which are related to inflammation, are dependent on IL-6 (254, 258), all studies indicate the intimate link between inflammation and tumorigenesis via IL-6–STAT3 signaling.”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [258]
Animal studies of energy balance support epidemiologic results relating obesity with cancer mortality.
“Similarly, animal studies of energy balance support epidemiologic results relating obesity with cancer mortality.”
From Diabetes and Cancer (2010) · cites this paper as [73]
Certain experimental cancers tend to behave more aggressively when animals overeat and less aggressively when animals are calorically restricted.
“Certain experimental cancers tend to behave more aggressively when animals overeat and less aggressively when animals are calorically restricted (72–74).”
From Diabetes and Cancer (2010) · cites this paper as [73]
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- Authors
- Park, E. J., Lee, J. H., Yu, G.-Y., He, G., Ali, S. R., Holzer, R. G., Österreicher, C. H., Takahashi, H., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Karin, Michael
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 140
- Issue
- 2
- Pages
- 197-208
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2836922
- OpenAlex
- W2080998956
- Cited by
- 1,764
- References
- 56
- Citations by year
- 2026: 52 · 2025: 77 · 2024: 89 · 2023: 101 · 2022: 107 · 2021: 119 · 2020: 115 · 2019: 113 · 2018: 121 · 2017: 130 · 2016: 134 · 2015: 102 · 2014: 121 · 2013: 116 · 2012: 118
- FWCI
- 60.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (WT086755)
- U.S. Public Health Service (20141835)
- National Cancer Institute (R01CA118165, CA118165)
- National Institute of Environmental Health Sciences (P42ES010337, R01ES006376)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- obesity, hepatocellular carcinoma, liver inflammation, carcinogenesis, interleukin-6, TNF-α, STAT3, diet-induced obesity, genetic obesity, chronic inflammation, cancer risk, tumor promoters
- MeSH terms
- Animals, Diethylnitrosamine, Female, Hepatitis, Carcinoma, Hepatocellular, Liver Neoplasms, Male, Obesity, Tumor Necrosis Factor-alpha, Interleukin-6, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, STAT3 Transcription Factor, Mice
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