Journal Article

Raloxifene inhibits adipose tissue inflammation and adipogenesis through Wnt regulation in ovariectomized rats and 3 T3-L1 cells

Wu, Hong-Min, Cheng, Pao-Yun, Lee, Yen-Mei, Yang, Chien-Yi, Kung, Ching-Wen, Lam, Kwok-Keung, Chen, Shu-Ying, Shen, Hsin-Hsueh

2019

Overview

Background Loss of ovarian function, as in menopause or after ovariectomy (OVX), is closely associated with obesity and white adipose tissue (WAT) inflammation. Estrogen replacement protects against postmenopausal obesity but increases the risks of carcinogenesis. In the present study, we investigated the effects of long-term treatment of raloxifene (RAL), a selective estrogen receptor modulator, on the features of estrogen deficiency-induced obesity and explored the involvement of canonical and non-canonical Wnt regulation in vivo and in vitro. Methods Adult female rats received bilateral OVX and divided into 5 groups: (1) Sham, (2) OVX, (3) OVX + E 2 : OVX rats were administered with E 2 (50 μg/kg, s.c., 3 times/week), (4) OVX + RAL: OVX rats were treated with RAL (gavage, 1 mg/kg/day) suspended in 0.8% carboxymethylcellulose (CMC), (5) OVX + CMC: 0.8% CMC as vehicle control. All treatments were given for 8 weeks beginning at 1 week after OVX. In 3 T3-L1 cells, the effects of RAL on adipogenesis and lipopolysaccharide (LPS)-induced inflammation were evaluated. Results Treatment with RAL significantly decreased body weight, visceral fat pad mass, adipocyte size and plasma levels of glucose but increased plasma adiponectin. RAL reduced the elevation of HIF-1α, VEGF-A and proinflammatory cytokines (MCP-1 and TNF-α) expression by inhibition of NF-κB p65 and JNK cascades in retroperitoneal WAT. This anti-inflammatory capacity of RAL may result from upregulation of secreted frizzle-related protein 5 (SFRP5), an adipokine that repressed Wnt5a signaling. Furthermore, RAL inhibited adipogenic factors such as PPAR-γ, C/EBP-α, and FABP4, and preserved canonical Wnt10b/β-catenin protein expression. In 3 T3-L1 adipocytes, RAL (20 μM) diminished lipid accumulation and inhibited adipogenic factors accompanied with the induction of β-catenin, which were effectively reversed by the β-catenin inhibitor IWR-1-endo. In addition, RAL reduced LPS-induced NF-κB p65 and p-IκB expression as well as TNF-α secretion. Suppression of SFRP5 by small interfering RNA significantly abrogated the anti-inflammatory effects of RAL. Conclusions Distinct activation of canonical β-catenin on inhibition of adipogenesis and non-canonical SFRP5 on suppression of WAT inflammation may contribute to the beneficial effects of RAL. Therefore, this study provides a rationale for the therapeutic potential of RAL for postmenopausal obesity.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 3T3-L1 Cells / Adipocytes / Adipogenesis / Adipogenesis - drug effects / Adiponectin / Adipose tissue / Adipose Tissue - drug effects / Adipose Tissue - immunology / Animals / Biomedical and Life Sciences / Biomedicine / Body weight / Carboxymethylcellulose / Carcinogenesis / Carcinogens / Cascades / CCAAT/enhancer-binding protein / Cytokines / Estrogen receptors / Estrogens / Female / Fuel consumption / Gene Expression Regulation / Health aspects / Hormone replacement therapy / In vitro methods and tests / In vivo methods and tests / Inflammation / Inflammation - chemically induced / Lipids / Lipopolysaccharides / Lipopolysaccharides - pharmacology / Menopause / Metabolic syndrome X / Mice / Monocyte chemoattractant protein 1 / NF-κB protein / Obesity / Ovariectomy / Peroxisome proliferator-activated receptors / Plasma levels / Post-menopause / Postmenopausal women / Proteins / Raloxifene / Raloxifene Hydrochloride - pharmacology / Rats / Rats, Wistar / Receptors, Estrogen - antagonists & inhibitors / Risk factors / Rodents / Selective Estrogen Receptor Modulators - pharmacology / siRNA / Tumor necrosis factor-α / Vascular endothelial growth factor / White adipose tissue / Wnt Proteins - genetics / Wnt Proteins - metabolism / Wnt1 Protein / Wnt10b