Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor.
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 beta-oxidation, increased de novo lipid synthesis arising from decreased PPARalpha, 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.


CONCLUSIONS
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.
Lin
Hung-Yun
HY
George Whipple Lab for Cancer Research, Department of Pathology, and Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Yu
I-Chen
IC
Wang
Ruey-Shen
RS
Chen
Yei-Tsung
YT
Liu
Ning-Chun
NC
Altuwaijri
Saleh
S
Hsu
Cheng-Lung
CL
Ma
Wen-Lung
WL
Jokinen
Jenny
J
Sparks
Janet D
JD
Yeh
Shuyuan
S
Chang
Chawnshang
C
D000375:Aging / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications / Q000209:etiology; D047493:PPAR alpha / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics
D004041:Dietary Fats; D005947:Glucose; D047493:PPAR alpha; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D011944:Receptors, Androgen; C069767:phosphoenolpyruvate carboxylase kinase; C516609:Ptpn1 protein, mouse