- 作者: Hsin-Hsueh Shen, Chien-Yi Yang, Ching-Wen Kung, Shu-Ying Chen, Hong-Min Wu, Pao-Yun Cheng, Kwok-Keung Lam and Yen-Mei Lee
- 作者服務機構: 1. Department and Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan 2. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 3. Department of Pharmacy Practice, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 4. Division of General Surgery, Department of Surgery, Tri-Service General Hospital Sungshan Branch, Taipei, Taiwan 5. Department of Nursing, Tzu Chi University of Science and Technology, Hualien, Taiwan 6. Department of Nursing, Hung Kuang University, Taichung, Taiwan 7. Department and Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan 8. Department of Physiology & Biophysics, National Defense Medical Center, Taipei, Taiwan 9. Department of Pharmacology, Taipei Medical University, Taipei, Taiwan 10.Department of Anesthesiology, Catholic Mercy Hospital, Hsinchu, Taiwan
- 中文摘要:
- 英文摘要:
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 + E2: OVX rats were administered with E2 (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. - 中文關鍵字:
- 英文關鍵字: Raloxifene, Menopause, Obesity, White adipose tissue, Inflammation, Wnt10b, β-Catenin, Wnt5a, SFRP5