Bazedoxifene and conjugated estrogen prevent diet-induced obesity, hepatic steatosis, and type 2 diabetes in mice without impacting the reproductive tract

Jose Barrera, Ken L. Chambliss, Mohamed Ahmed, Keiji Tanigaki, Bonne Thompson, Jeffrey G. McDonald, Chieko Mineo, Philip W. Shaul

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 + 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 + 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 + BZA. Whereas E2 or CE alone invoked a uterotrophic response, BZA alone or CE + BZA had negligible impact on the uterus. Thus, CE + 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume307
Issue number3
DOIs
StatePublished - Aug 1 2014

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Conjugated (USP) Estrogens
Type 2 Diabetes Mellitus
Obesity
Diet
Liver
Body Composition
Homeostasis
Glucose
Estrogens
bazedoxifene
Selective Estrogen Receptor Modulators
White Adipose Tissue
Intra-Abdominal Fat
Adiposity
Fatty Liver
Glucose Tolerance Test
Pyruvic Acid
Weight Gain
Uterus
Insulin Resistance

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

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abstract = "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 + 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 + 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 + BZA. Whereas E2 or CE alone invoked a uterotrophic response, BZA alone or CE + BZA had negligible impact on the uterus. Thus, CE + 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.",
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AU - Chambliss, Ken L.

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AU - Tanigaki, Keiji

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AU - McDonald, Jeffrey G.

AU - Mineo, Chieko

AU - Shaul, Philip W.

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