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Insulin and Leptin Resistance With Hyperleptinemia in Mice Lacking Androgen Receptor

University of Rochester Medical Center, the George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology, and the Cancer Center, Rochester, New York

Epidemiological evidence suggests that sex differences exist in type 2 diabetes. Men seem to be more susceptible than women to the consequences of obesity and sedentary lifestyle, possibly because of differences in insulin sensitivity and regional body fat deposition. Thus, lacking androgen receptor (AR) in male individuals may promote insulin resistance. To determine whether lacking AR in male individuals contributes to in vivo insulin resistance, an AR knockout model (AR^–/y) was used to study the correlation between AR and insulin resistance. Progressive reduced insulin sensitivity and impaired glucose tolerance were seen in AR^–/y mice with advancing age. Aging AR^–/y mice displayed accelerated weight gain, hyperinsulinemia, and hyperglycemia, and loss of AR contributes to increased triglyceride content in skeletal muscle and liver. Leptin is higher in serum of AR^–/y mice. Treatment with exogenous leptin fails to stimulate weight loss in AR^–/y mice in advanced age, suggesting leptin resistance in the AR^–/y/ mice. Exogenous dihydrotestosterone replacement fails to reverse the metabolic abnormalities and insulin resistance in AR^–/y mice. Our in vivo studies demonstrate that androgen-AR plays key roles in the development of insulin and leptin resistance, which may contribute to the development of type 2 diabetes and cardiovascular disease.

Abbreviations: AR, androgen receptor; GTT, glucose tolerance test; ITT, insulin tolerance test; PI3K, phosphoinositide-3-OH kinase; PPAR, peroxisome proliferator–activated receptor; TNF-, tumor necrosis factor-; WAT, white adipose tissue

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