Abstract 15885: The Novel Selective Estrogen Receptor Modulator Bazedoxifene Provides Protection From Diet-Induced Obesity and Type 2 Diabetes in Mice Without Impacting the Reproductive Tract
Despite the potent capacity of estrogen to favorably regulate energy homeostasis and glucose metabolism, the use of the hormone to combat obesity and type 2 diabetes is not feasible because it promotes sex steroid-responsive cancers. In contrast to estrogen, the novel selective estrogen receptor modulator (SERM) bazedoxifene (BZA) uniquely antagonizes both breast cancer development and estrogen-related changes in the female reproductive tract. Whether BZA impacts metabolism is unknown. In the present study we determined how BZA, conjugated estrogen (CE), which is the form of estrogen routinely used clinically, and BZA+CE affect body composition and glucose homeostasis in mice. Females were ovariectomized at 4 weeks of age, treatment was initiated, and the mice were placed on a high fat/high cholesterol western diet for 12 weeks. In contrast to vehicle, estradiol (E2), CE, BZA, and BZA+CE equally prevented body weight gain by 50%. In parallel, E2, CE, BZA, and BZA+CE caused dramatic equal prevention of the 3-fold increase in body fat mass invoked by the western diet, as well as the increases in subcutaneous and visceral white adipose tissue. Whereas adipocyte size was increased by western diet in vehicle-treated mice, this was also comparably prevented by E2, CE, BZA, or BZA+CE. Liver steatosis was attenuated by E2 or CE, and BZA either alone or with CE provided even greater prevention of steatosis. Elevations in fasting glucose and insulin were most dramatically prevented by E2, CE, and BZA+CE, whereas BZA alone had modest effect. Similarly, glucose tolerance tests were most markedly improved in response to E2, CE, and BZA+CE, and BZA alone had modest effect. Importantly, although E2 or CE caused a dramatic increase in uterine weight, BZA alone or BZA+CE had no impact on the uterus. Thus, BZA and BZA+CE afford potent protection from diet-induced obesity in mice equal to that provided by E2 or CE. In contrast, whereas E2, CE alone and BZA+CE cause dramatic improvement in glucose tolerance, BZA alone has modest beneficial impact on glucose metabolism. Thus, BZA alone may be a valuable new therapy to prevent obesity, and BZA+CE may provide an important new means to prevent both obesity and type 2 diabetes without increasing the risk of sex steroid-responsive cancers.
- © 2013 by American Heart Association, Inc.