Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-11-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877818306781 |
| _version_ | 1818695477109981184 |
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| author | Melanie J. Mittenbühler Hans-Georg Sprenger Sabine Gruber Claudia M. Wunderlich Lara Kern Jens C. Brüning F. Thomas Wunderlich |
| author_facet | Melanie J. Mittenbühler Hans-Georg Sprenger Sabine Gruber Claudia M. Wunderlich Lara Kern Jens C. Brüning F. Thomas Wunderlich |
| author_sort | Melanie J. Mittenbühler |
| collection | DOAJ |
| description | 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: We demonstrate that both high-fat diet (HFD)-induced obesity and IL-6Rα deficiency induce hepatic Lepr expression. Consistently, double knockout mice show a further reduction in tumor burden in DEN-induced HCC when compared to control and single LepRL−KO/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. Keywords: Hepatic leptin receptor, Ob-R, Hepatocellular carcinoma, IL-6Rα deficiency, Obesity |
| first_indexed | 2024-12-17T13:46:05Z |
| format | Article |
| id | doaj.art-774ace42901d46259223257b2842c3ed |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-17T13:46:05Z |
| publishDate | 2018-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-774ace42901d46259223257b2842c3ed2022-12-21T21:46:09ZengElsevierMolecular Metabolism2212-87782018-11-0117122133Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinomaMelanie J. Mittenbühler0Hans-Georg Sprenger1Sabine Gruber2Claudia M. Wunderlich3Lara Kern4Jens C. Brüning5F. Thomas Wunderlich6Max Planck Institute for Metabolism Research, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Cologne, 50931, GermanyExcellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Germany; Max Planck Institute for Biology of Ageing, Cologne, 50931, GermanyMax Planck Institute for Metabolism Research, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Cologne, 50931, GermanyMax Planck Institute for Metabolism Research, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Cologne, 50931, GermanyMax Planck Institute for Metabolism Research, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Cologne, 50931, GermanyMax Planck Institute for Metabolism Research, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Cologne, 50931, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), GermanyMax Planck Institute for Metabolism Research, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Cologne, 50931, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Germany; Corresponding author.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: We demonstrate that both high-fat diet (HFD)-induced obesity and IL-6Rα deficiency induce hepatic Lepr expression. Consistently, double knockout mice show a further reduction in tumor burden in DEN-induced HCC when compared to control and single LepRL−KO/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. Keywords: Hepatic leptin receptor, Ob-R, Hepatocellular carcinoma, IL-6Rα deficiency, Obesityhttp://www.sciencedirect.com/science/article/pii/S2212877818306781 |
| spellingShingle | Melanie J. Mittenbühler Hans-Georg Sprenger Sabine Gruber Claudia M. Wunderlich Lara Kern Jens C. Brüning F. Thomas Wunderlich Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma Molecular Metabolism |
| title | Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma |
| title_full | Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma |
| title_fullStr | Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma |
| title_full_unstemmed | Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma |
| title_short | Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma |
| title_sort | hepatic leptin receptor expression can partially compensate for il 6rα deficiency in den induced hepatocellular carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S2212877818306781 |
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