Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice

Abstract

Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.

Mitochondrial Quality Control as a Therapeutic Target

“…Bazedoxifene with conjugated E2 is a combination of selective tissue E2 complexes and receptor modulator that provides tissuespecific benefits of E2 in menopausal osteoporosis in women (Archer, 2010) and improves cardiovascular disease risk and metabolic syndrome with greater effects in endometrium and breast in animal models (Barrera et al, 2014;Kim et al, 2014). Although selective tissue E2 complexes are still in trials, newer, more innovative, efficient, and tissue-specific E2 receptor agonists are being investigated.…”

Effect of selective estrogen receptor modulators on metabolic homeostasis

“…The impact of CE/BZA on metabolic parameters has been studied in ovariectomized (OVX) female mice. In OVX mice, CE/BZA and even BZA alone significantly attenuated OVX-induced body weight increase [67e69], and the accumulation of subcutaneous and visceral fat [67,68] without modifying lean body mass level [68].…”

“…Additionally, the combination of CE/BZA improved hepatic lipid homeostasis in OVX mice by decreasing hepatic triglyceride accumulation [67,68]. The reduction of hepatic steatosis following CE/ BZA treatment was the result of a suppressed de novo fatty acid synthesis, which was secondary to a decreased fatty acid synthase (FAS) expression and enzyme activity [67].…”

“…The reduction of hepatic steatosis following CE/ BZA treatment was the result of a suppressed de novo fatty acid synthesis, which was secondary to a decreased fatty acid synthase (FAS) expression and enzyme activity [67]. As a result, hepatic free fatty acid accumulation was repressed in OVX mice treated with CE/ BZA [70].…”

“…The combination CE/BZA also boosted lipid oxidation in liver through multiple critical pathways involved in lipid metabolism [67]. First, CE/BZA enhanced hepatic production and action of fibroblast growth factor-21 (FGF21), which plays an important role in stimulating hepatic lipid oxidation [71].…”