gated estrogen prevent diet-induced obesity, hepatic steatosis, and type 2 diabetes in mice without impacting the reproductive tract. Am J Physiol Endocrinol Metab 307: E345-E354, 2014. First published June 17, 2014 doi:10.1152/ajpendo.00653.2013.-Despite the capacity of estrogens to favorably regulate body composition and glucose homeostasis, their use to combat obesity and type 2 diabetes is not feasible, because they promote sex steroid-responsive cancers. The novel selective estrogen receptor modulator (SERM) bazedoxifene acetate (BZA) uniquely antagonizes both breast cancer development and estrogen-related changes in the female reproductive tract. How BZA administered with conjugated estrogen (CE) or alone impacts metabolism is unknown. The effects of BZA or CE ϩ BZA on body composition and glucose homeostasis were determined in ovariectomized female mice fed a Western diet for 10 -12 wk. In contrast to vehicle, estradiol (E2), CE, BZA, and CE ϩ BZA equally prevented body weight gain by 50%. In parallel, all treatments caused equal attenuation of the increase in body fat mass invoked by the diet as well as the increases in subcutaneous and visceral white adipose tissue. Diet-induced hepatic steatosis was attenuated by E2 or CE, and BZA alone or with CE provided even greater steatosis prevention; all interventions improved pyruvate tolerance tests. Glucose tolerance tests and HOMA-IR were improved by E2, CE, and CE ϩ BZA. Whereas E2 or CE alone invoked a uterotrophic response, BZA alone or CE ϩ BZA had negligible impact on the uterus. Thus, CE ϩ BZA affords protection from diet-induced adiposity, hepatic steatosis, and insulin resistance with minimal impact on the female reproductive tract in mice. These combined agents may provide a valuable new means to favorably regulate body composition and glucose homeostasis and combat fatty liver. bazedoxifene; conjugated estrogen; hepatic steatosis; obesity; type 2 diabetes IN ADDITION TO THEIR ROLES in sexual development and reproduction, estrogens contribute to the regulation of body weight and body composition and to glucose homeostasis. Insulin sensitivity is greater in women prior to menopause vs. agematched men (16,42), in women the risk for weight gain and for the development of type 2 diabetes increases with the decline in the levels of estrogens that occurs at menopause, and menopause favors an increase in total body fat and visceral fat deposition (4). In addition, hormone replacement therapy with conjugated estrogen (CE) and medroxyprogesterone acetate (MPA) in postmenopausal women causes a 21-35% decrease in diabetes occurrence (29,35). Furthermore, in female rodents and primates, ovariectomy results in impaired insulin sensitivity and glucose homeostasis, and these effects are reversed by estradiol (E 2 ) (30, 54). Studies in mice have additionally demonstrated that E 2 provides potent protection against highfat diet-induced glucose intolerance and insulin resistance (46). The metabolic actions of estrogens are mediated primarily by estrogen receptor (E...