Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor

Authors

  • Hung-Yun Lin,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    Search for more papers by this author
    • These authors contributed equally to this study.

  • I-Chen Yu,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    Search for more papers by this author
    • These authors contributed equally to this study.

  • Ruey-Shen Wang,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    2. Department of Gynecology and Obstetrics, Taipei Medical University, Taipei, Taiwan
    Search for more papers by this author
  • Yei-Tsung Chen,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    Search for more papers by this author
  • Ning-Chun Liu,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    Search for more papers by this author
  • Saleh Altuwaijri,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    Search for more papers by this author
  • Cheng-Lung Hsu,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    2. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
    Search for more papers by this author
  • Wen-Lung Ma,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    Search for more papers by this author
  • Jenny Jokinen,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    Search for more papers by this author
  • Janet D. Sparks,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    Search for more papers by this author
  • Shuyuan Yeh,

    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    Search for more papers by this author
  • Chawnshang Chang

    Corresponding author
    1. George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and the Cancer Center, University of Rochester Medical Center, Rochester, NY
    • 601 Elmwood Avenue, Box 626, Rochester, NY 14642
    Search for more papers by this author
    • fax: (585) 756-4133


  • Potential conflict of interest: Nothing to report.

Abstract

Early studies demonstrated that whole-body androgen receptor (AR)–knockout mice with hypogonadism exhibit insulin resistance. However, details about the mechanisms underlying how androgen/AR signaling regulates insulin sensitivity in individual organs remain unclear. We therefore generated hepatic AR-knockout (H-AR−/y) mice and found that male H-AR−/y mice, but not female H-AR−/− mice, fed a high-fat diet developed hepatic steatosis and insulin resistance, and aging male H-AR−/y mice fed chow exhibited moderate hepatic steatosis. We hypothesized that increased hepatic steatosis in obese male H-AR−/y mice resulted from decreased fatty acid β-oxidation, increased de novo lipid synthesis arising from decreased PPARα, increased sterol regulatory element binding protein 1c, and associated changes in target gene expression. Reduced insulin sensitivity in fat-fed H-AR−/y mice was associated with decreased phosphoinositide-3 kinase activity and increased phosphenolpyruvate carboxykinase expression and correlated with increased protein-tyrosine phosphatase 1B expression. Conclusion: Together, our results suggest that hepatic AR may play a vital role in preventing the development of insulin resistance and hepatic steatosis. AR agonists that specifically target hepatic AR might be developed to provide a better strategy for treatment of metabolic syndrome in men. (HEPATOLOGY 2008.)

Ancillary