SAT-024 Adipose Specific Inactivation of Aromatase is Sufficient to Cause Adiposity and Impaired Glucose Tolerance in Mice

Abstract

Aromatase synthesizes estrogens from androgens. While the gonads are major sites of aromatase expression, it is expressed in multiple other organs including adipose tissue, brain and bone. In global aromatase knockouts in mice, studied by us, or man aromatase deficiency there are phenotypes of adiposity and low bone mass as well as varying degrees of insulin resistance. Breast cancer patients treated with aromatase inhibitors (AIs) also develop adiposity and low bone mass. Thus, it remains unclear the role of site specific aromatase activity in the phenotypes observed in chemically or genetically induced aromatase deficiency. To begin to understand the relative contributions of tissue specific aromatase activity and develop a model that will be useful for understanding and developing therapeutic strategies for ailments in aromatase inhibitor therapy, we have developed mouse models with tissue specific aromatase inactivation. Embryonic stem cells were purchased from EUCOMM. Using standard methods and appropriate breeding strategies we generated C57Bl6 mice with Lox P sites flanking Exon 2 in the aromatase gene (Arom fl/fl). Mice with adipose specific inactivation of aromatase were generated by interbreeding Arom fl/fl mice with mice expressing Cre recombinase driven by the adiponectin promoter (AdipoCre). We measured body composition by dual energy x-ray absorptiometry (Lunar PIXIMus 2). As a first step in examining glucose homeostasis we performed oral glucose tolerance tests. All mice were fed normal chow and the study was approved by the local IACUC. Female mice aged 4-6 months were studied with at least 4 animals in each group. Arom fl/fl mice were compared as controls for the AdipoCre+; Arom fl/fl mice. Mean body weight was higher in fat specific aromatase knockout female mice (33.6 vs 21.6, p<0.05). On DEXA Mean %Body fat was higher in female AdipoCre+;Arom fl/fl mice (29.3% vs. 17.3%, p<0.05). Following a 16h fast female mice with adipose specific aromatase inactivation had higher fasting blood glucose levels (93.3+/-10.3 vs 74.5+/-10, p=0.03). For the glucose tolerance test, a bolus of glucose (2 g/kg) was delivered into the stomach by a gavage needleand blood was sampled at 0, 5, 10, 20, 30, 60, 90, 120, and 180 min for plasma glucose analyses. On OGTT peak glucose levels were higher and did not return to baseline. Insulin tolerance tests will be performed to further understand the mechanism of impaired glucose homeostasis. Male mice with fat specific aromatase inactivation showed similar patterns in higher body weight, percent body fat and glucose levels but the phenotype was more variable. In summary, fat specific aromatase inactivation is sufficient to cause adiposity and impaired glucose homeostasis. The observed phenotype in females is more robust than we have observed in the global knockout.