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研究生:沈信學
研究生(外文):Shen, Hsin-Hsueh
論文名稱:選擇性雌性素接受器調節劑對停經肥胖及代謝症候群之療效及機轉探討
論文名稱(外文):Investigation of the protective effects and mechanisms of the selective estrogen modulator in menopausal obesity and metabolic syndromes
指導教授:李燕媚
指導教授(外文):Lee, Yen-Mei
口試委員:謝博軒曾清俊許準榕洪乙仁
口試委員(外文):Hsieh, Po-ShiuanTseng, Ching-JiunnSheu, Joen-RongHung, Yi-Jen
口試日期:2020-05-14
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:英文
論文頁數:99
中文關鍵詞:停經肥胖脂肪發炎胰島素抗性白色脂肪棕色化
外文關鍵詞:menopauseobesityadipose tissue inflammationinsulin resistancewhite adipose tissue browning
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停經婦女因雌性素缺乏,易導致肥胖以及胰島素抗性等代謝症候群,然而荷爾蒙替代療法 (HRT)雖可有效改善停經症狀,但卻易引發子宮內膜癌以及乳癌產生。本論文的研究目的在探討以卵巢切除動物模式(OVX)誘發雌性素缺乏而引起母鼠肥胖,探討raloxifene (RAL)及genistein (GEN)等雌性素製劑對於停經肥胖以及脂肪發炎之保護作用,及誘導白色脂肪棕色化之產熱機制。
第一部分實驗:7週大母鼠進行雙側卵巢切除手術,術後皮下注射17-β estradiol (50 g/kg, 每週3次)或管灌餵食RAL (1mg/kg),給藥時間共計8週。在細胞實驗中將3T3-L1細胞誘導分化成為脂肪細胞,並給予RAL 探討藥物對於脂肪新生以及改善給與LPS誘發脂肪細胞發炎之抗炎機制; (2)卵巢切除鼠合併高脂肪飲食 (45% fat),並給予GEN (15mg or 30mg/kg/day) 4週,探討GEN誘導白色脂肪棕色化來達到降低體重、改善脂肪細胞發炎肝臟脂質新生及胰島素抗性效果。結果顯示RAL 可降低卵巢切除鼠體重增加、臟器脂肪量、腹膜後脂肪細胞粒徑以及血中葡萄糖,並且增加血漿中adiponectin的量。RAL可降低腹膜後脂肪組織HIF-1α及其下游VEGF-A蛋白質表現,促發炎激素TNF-α與MCP-1蛋白表現明顯被抑制; 發炎路徑NF-κB p65以及pJNK蛋白表現也明顯被抑制,可能與誘導SFRP5之抗發炎機制有關。在調控脂肪新生中,RAL可抑制脂質新生調節因子PPAR-γ, C/EBP-α以及FABP4之蛋白表現,並誘導典型Wnt路徑之Wnt10b與β-catenin的蛋白生成。在細胞實驗中,3T3-L1細胞分化過程,RAL 20 M濃度可明顯抑制脂質堆積、降低PPAR-γ, C/EBP-α以及FABP4之蛋白表現,以及誘導β-catenin的蛋白生成。合併給予RAL 與IWR-1 endo (20 μM, β-catenin 抑制劑)明顯減低RAL抑制脂肪新生之效果,因此推論RAL 抑制脂肪新生之作用可能是透過β-catenin調節所致。在脂肪發炎部分,給予LPS (10g/mL)刺激脂肪細胞發炎,並同時給予RAL 20 M後,RAL可明顯誘導SFRP5蛋白生成,降低NF-κB p65以及pIκB蛋白表現,並減少細胞培養液之TNF-α 釋放。以siRNA 基因沉默SFRP5 後,RAL 改善上述的發炎現象明顯被抑制,因此可知RAL之抗發炎機制乃是透過誘導SFRP5生成導致⸰
第二部分實驗:卵巢切除大鼠合併高脂肪飲食(45%脂肪),再給予GEN 30 mg/kg,於4周後,明顯改善體重增加及胰島素抗性,並增加腹膜後白色脂肪之p-IRS1與p-AKT之蛋白表現。GEN可降低脂肪細胞肥大、抑制促發炎細胞激素 MCP-1, TNF-α與IL-6 釋放,並且抑制NF-κB路徑之活化。GEN可增加血漿中鳶尾素irisin 之釋放,以及增加腹股溝脂肪UCP1, PRDM16, PGC-1α 與CIDEA之蛋白質表現; 亦可增加Ppargc1a, Ucp-1 與 Tbx-1 等mRNA表現,其機轉可能與細胞核內ERα增加有關。在血脂及肝臟脂肪堆積部分,GEN可降低血漿三酸甘油酯(TGs)與總膽固醇(cholesterol),並抑制肝臟脂質新生相關蛋白p-ACC, SREBP1c, FAS與CD36蛋白質表現。結論: RAL與GEN等雌性素相關製劑可降低停經肥胖,進而改善停經代謝症候群之發生。

Loss of ovarian function, as in menopause or after ovariectomy (OVX) operation, exhibits a higher prevalence of obesity and insulin resistance than that of premenopausal status. It is reported that Wingless-type MMTV integration site family members (Wnts)signaling plays an important role in regulating adipocyte homeostasis, adipogenesis and inflammation. Raloxifene (RAL) is the second generation of selective estrogen receptor modulator (SERM) and clinically approved for the prevention of osteoporosis during menopause. Phytoestrogen genistein (GEN) is structurally and functionally similar to estrogen via activating nuclear estrogen receptor (ER). In the present study, we investigated the effects of long-term treatment of RAL (Experiment 1) or GEN (Experiment 2) on the features of estrogen deficiency-induced obesity and explored the underlying mechanism.
Experiment 1: Adult female rats received bilateral OVX and were divided into 5 groups: (1) Sham, (2) OVX, (3) OVX+E2: OVX rats were administered with E2 (50 g/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 vitro study, 3T3-L1 cells were obtained to investigate the cause 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 levels. RAL reduced the elevation of HIF-1, VEGF-A and proinflammatory cytokines (MCP-1 and TNF-) expression by inhibition of NF-B and p-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-, C/EBP- and FABP4, and preserved canonical Wnt10b/-catenin protein expression. In 3T3-L1 adipocytes, RAL (20 M) diminished lipid accumulation and inhibited adipogenic factors accompanied by the induction of -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- secretion. Suppression of SFRP5 by small interfering RNA significantly abrogated the anti-inflammatory effects of RAL. Our preliminary results also showed that administration with RAL (10 M) increased brown fat specific markers UCP-1, PRDM16, PGC-1 and CIDEA protein expression in differentiated 3T3-L1 adipocytes.
Experiment 2: We aimed to investigate the effects of phytoestrogen genistein (GEN) on white adipose tissue (WAT) inflammation, browning and hepatic lipogenesis in ovariectomized rats with high fat diet (HFD) and further explore the underlying mechanism. Female Wistar rats received ovariectomy (Ovx) and HFD (45% fat) and then administered with 17β-estradiol (E2, 3 times/week, sc) or GEN (15 mg/kg or 30 mg/kg, gavage, once daily) for 4 weeks. Administration of GEN decreased Ovx-induced body weight gain, adiposity and improved insulin sensitivity as well as increased insulin signaling p-IRS1 and p-AKT in retroperitoneal WAT. Adipocyte hypertrophy and proinflammatory cytokines MCP-1, TNF-α, and IL-6 production were reduced by GEN. It also suppressed the activation of NF-κB pathway, evidenced by attenuation of p65 and pIκB levels. Additionally, GEN elevated myokine irisin and promoted WAT browning by increasing UCP-1, PRDM-16, PGC-1α and CIDEA proteins and Ppargc1a, Ucp-1 and Tbx-1 mRNA in inguinal WAT which is associated with upregulation of nuclear estrogen receptor-α. Plasma levels of triglyceride and cholesterol were reduced by GEN treatment accompanied with inhibition of lipogenic proteins (p-ACC, SREBP-1, FAS and CD36) in the liver.
In conclusion, RAL ameliorated estrogen deficiency-induced obesity and WAT inflammation via Wnt sigaling and GEN attenuated estrogen deficiency-induced obesity, WAT inflammation, hepatic lipogenesis, and promoted WAT browning. They may provide a promising approach to prevent obesity and metabolic syndromes during menopause.

圖目錄 (Lists of Figures) iv
中文摘要 viii
Abstract xi
Abbreviations xiv
Introduction 1
I.Menopause and related metabolic syndromes 1
II.Obesity, adipose tissue and insulin resistance 2
III.Adipose tissue browning in the regulation of metabolic homeostasis 4
IV.Wnt signaling pathways in metabolic regulation 5
1.Canonical Wnt signaling 5
2.Non-canonical Wnt signaling 7
V.Adipose tissue browning 8
VI.Selective estrogen receptor modulators (SERMs) and phytoestrogen 10
1.Hormone replacement therapy 10
2.Therapeutic aspects of raloxifene 10
3.Therapeutic overview of phytoestrogen genistein 11
Aim of the present study 13
Materials and methods 15
Animal preparation 15
Bilateral ovariectomy procedure in female rats 15
Experimental groups: Part I 16
Experimental groups: Part II 16
Oral glucose tolerance test 17
Measurement of plasma levels of estrogen, adiponectin, insulin, glucose, irisin, triglyceride and total cholesterol 17
Histological analysis and immunohistochemistry stain 18
Preparation of nuclear extracts 18
Western blot analysis 18
RNA extraction and quantitative–Real Time PCR 19
Cell culture and differentiation of 3T3-L1 cells 20
Cell viability assay 21
Oil Red O Staining 21
Transfection with small interfering (si) RNA for SFRP5 knockdown in 3T3-L1 cells 21
Enzyme-linked immunosorbent assay (ELISA) of TNF-α in conditioned medium of 3T3-L1 cells 21
Statistical analysis 22
Results-Part I 23
1.1. Effects of RAL on the levels of plasma E2, body weight (BW) and total visceral fat pad mass in OVX rats 23
1.2. Effects of RAL on plasma levels of adiponectin and glucose in OVX rats 24
1.3. Effects of RAL on adipocyte size in OVX rats 24
1.4. Effects of RAL on adipocyte hypertrophy-induced inflammatory responses in OVX rats 24
1.5. Effects of RAL on non-canonical SFRP5 and Wnt5a expression in OVX rats 26
1.6. Effects of RAL on adipogenic differentiation and canonical Wnt signaling in OVX rats 26
1.7. Effects of RAL on lipid accumulation and adipogenesis in 3T3-L1 cells 27
1.8. SFRP5 silencing blunted the suppressive effects of RAL on LPS-induced inflammation in 3T3-L1 cells 28
1.9. Effects of RAL on the conversion of white to beige adipocytes in 3T3-L1 cells 28
Results-Part II 29
2.1. Effects of GEN on body weight and food intake in Ovx rats with HFD 29
2.2. Effects of GEN on brown, inguinal and total visceral WAT weight 29
2.3. Effects of GEN on OGTT, plasma levels of insulin and adiponectin in Ovx rats 30
2.4.GEN reduced adipocyte sizes and inflammation through NF-B pathway in retroperitoneal WAT of Ovx rats 30
2.5. GEN increased the phosphorylation of insulin receptor substrate-1 and AKT in retroperitoneal WAT of Ovx rats 31
2.6. Effects of GEN on H&E staining and immunohistochemistry for UCP-1 in inguinal WAT of Ovx rats 31
2.7. GEN increased plasma irisin levels and transcriptional regulators of browning in inguinal WAT of Ovx rats 32
2.8. Effects of GEN on plasma lipid levels and hepatic lipogenesis in OVX rats 33
Discussion 34
Conclusion and perspective 48
References 49


References
Arteaga, E., Villaseca, P., Bianchi, M., et al. 2003. Raloxifene is a better antioxidant of low-density lipoprotein than estradiol or tamoxifen in postmenopausal women in vitro. Menopause, 10, 142-6.
Aziz, S. A., Wakeling, L. A., Miwa, S., et al. 2017. Metabolic programming of a beige adipocyte phenotype by genistein. Mol Nutr Food Res, 61.
Barros, R. P., Gabbi, C., Morani, A., et al. 2009. Participation of ERalpha and ERbeta in glucose homeostasis in skeletal muscle and white adipose tissue. Am J Physiol Endocrinol Metab, 297, E124-33.
Bartelt, A. & Heeren, J. 2014. Adipose tissue browning and metabolic health. Nat Rev Endocrinol, 10, 24-36.
Bennett, C. N., Longo, K. A., Wright, W. S., et al. 2005. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A, 102, 3324-9.
Bennett, C. N., Ross, S. E., Longo, K. A., et al. 2002. Regulation of Wnt signaling during adipogenesis. J Biol Chem, 277, 30998-1004.
Bhupathiraju, S. N. & Hu, F. B. 2016. Epidemiology of Obesity and Diabetes and Their Cardiovascular Complications. Circ Res, 118, 1723-35.
Bilkovski, R., Schulte, D. M., Oberhauser, F., et al. 2011. Adipose tissue macrophages inhibit adipogenesis of mesenchymal precursor cells via wnt-5a in humans. Int J Obes (Lond), 35, 1450-4.
Bitto, A., Altavilla, D., Bonaiuto, A., et al. 2009. Effects of aglycone genistein in a rat experimental model of postmenopausal metabolic syndrome. J Endocrinol, 200, 367-76.
Black, L. J., Sato, M., Rowley, E. R., et al. 1994. Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest, 93, 63-9.
Bostrom, P., Wu, J., Jedrychowski, M. P., et al. 2012. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481, 463-8.
Bryzgalova, G., Gao, H., Ahren, B., et al. 2006. Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia, 49, 588-97.
Bryzgalova, G., Lundholm, L., Portwood, N., et al. 2008. Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab, 295, E904-12.
Cannon, B. & Nedergaard, J. 2004. Brown adipose tissue: function and physiological significance. Physiol Rev, 84, 277-359.
Cao, L., Choi, E. Y., Liu, X., et al. 2011. White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metab, 14, 324-38.
Cardona-Gomez, P., Perez, M., Avila, J., et al. 2004. Estradiol inhibits GSK3 and regulates interaction of estrogen receptors, GSK3, and beta-catenin in the hippocampus. 25, 363-373.
Carr, M. C. 2003. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab, 88, 2404-11.
Catalan, V., Gomez-Ambrosi, J., Rodriguez, A., et al. 2014. Activation of noncanonical Wnt signaling through WNT5A in visceral adipose tissue of obese subjects is related to inflammation. J Clin Endocrinol Metab, 99, E1407-17.
Chen, B., Dodge, M. E., Tang, W., et al. 2009. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol, 5, 100-7.
Chen, L. & Chen, R. 2015. Mechanisms Linking Inflammation to Insulin Resistance. 2015, 508409.
Choi, J. S. & Song, J. 2009. Effect of genistein on insulin resistance, renal lipid metabolism, and antioxidative activities in ovariectomized rats. Nutrition, 25, 676-85.
Christodoulides, C., Lagathu, C., Sethi, J. K., et al. 2009. Adipogenesis and WNT signalling. Trends Endocrinol Metab, 20, 16-24.
Chung, M. T., Cheng, P. Y., Lam, K. K., et al. 2010. Cardioprotective effects of long-term treatment with raloxifene, a selective estrogen receptor modulator, on myocardial ischemia/reperfusion injury in ovariectomized rats. Menopause, 17, 127-34.
Chung, S. S., Lee, J. S., Kim, M., et al. 2012. Regulation of Wnt/beta-catenin signaling by CCAAT/enhancer binding protein beta during adipogenesis. Obesity (Silver Spring), 20, 482-7.
Cj, B. 1998. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet, 351, 1451-67.
Colditz, G. A., Hankinson, S. E., Hunter, D. J., et al. 1995. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med, 332, 1589-93.
Cucinelli, F., Soranna, L., Romualdi, D., et al. 2002. The effect of raloxifene on glyco-insulinemic homeostasis in healthy postmenopausal women: a randomized placebo-controlled study. J Clin Endocrinol Metab, 87, 4186-92.
Cypess, A. M., Lehman, S., Williams, G., et al. 2009. Identification and importance of brown adipose tissue in adult humans. N Engl J Med, 360, 1509-17.
Della Torre, S., Mitro, N., Fontana, R., et al. 2016. An Essential Role for Liver ERalpha in Coupling Hepatic Metabolism to the Reproductive Cycle. Cell Rep, 15, 360-71.
Disaia, P. J. & Brewster, W. R. 2002. Hormone replacement therapy for survivors of breast and endometrial cancer. Curr Oncol Rep, 4, 152-8.
Dowal, L., Parameswaran, P., Phat, S., et al. 2017. Intrinsic Properties of Brown and White Adipocytes Have Differential Effects on Macrophage Inflammatory Responses. Mediators Inflamm, 2017, 9067049.
Engeli, S., Feldpausch, M., Gorzelniak, K., et al. 2003. Association between adiponectin and mediators of inflammation in obese women. Diabetes, 52, 942-7.
Fabbrini, E., Sullivan, S. & Klein, S. 2010. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology, 51, 679-89.
Farmer, S. R. 2005. Regulation of PPARgamma activity during adipogenesis. Int J Obes (Lond), 29 Suppl 1, S13-6.
Farmer, S. R. 2008. Molecular determinants of brown adipocyte formation and function. Genes Dev, 22, 1269-75.
Flegal, K. M., Carroll, M. D., Ogden, C. L., et al. 2010. Prevalence and trends in obesity among US adults, 1999-2008. Jama, 303, 235-41.
Fontana, L., Eagon, J. C., Trujillo, M. E., et al. 2007. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes, 56, 1010-3.
Francucci, C. M., Daniele, P., Iori, N., et al. 2005. Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women. J Endocrinol Invest, 28, 623-31.
Fu, Z., Gilbert, E. R., Pfeiffer, L., et al. 2012. Genistein ameliorates hyperglycemia in a mouse model of nongenetic type 2 diabetes. Appl Physiol Nutr Metab, 37, 480-8.
Fuster, J. J., Zuriaga, M. A., Ngo, D. T., et al. 2015. Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes, 64, 1235-48.
Gao, B., Huang, Q., Lin, Y. S., et al. 2014. Dose-dependent effect of estrogen suppresses the osteo-adipogenic transdifferentiation of osteoblasts via canonical Wnt signaling pathway. PLoS One, 9, e99137.
Gizzo, S., Saccardi, C., Patrelli, T. S., et al. 2013. Update on raloxifene: mechanism of action, clinical efficacy, adverse effects, and contraindications. Obstet Gynecol Surv, 68, 467-81.
Godsland, I. F. 2005. Oestrogens and insulin secretion. Diabetologia, 48, 2213-20.
Gormsen, L. C., Høst, C., Hjerrild, B. E., et al. 2012. Estradiol acutely inhibits whole body lipid oxidation and attenuates lipolysis in subcutaneous adipose tissue: a randomized, placebo-controlled study in postmenopausal women. Eur J Endocrinol, 167, 543-51.
Gruber, C. J., Tschugguel, W., Schneeberger, C., et al. 2002. Production and actions of estrogens. N Engl J Med, 346, 340-52.
Guo, S. 2014. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms. J Endocrinol, 220, T1-t23.
Halberg, N., Khan, T., Trujillo, M. E., et al. 2009. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol, 29, 4467-83.
Harmon, A. W. & Harp, J. B. 2001. Differential effects of flavonoids on 3T3-L1 adipogenesis and lipolysis. Am J Physiol Cell Physiol, 280, C807-13.
He, Q., Gao, Z., Yin, J., et al. 2011. Regulation of HIF-1{alpha} activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. Am J Physiol Endocrinol Metab, 300, E877-85.
Heine, P. A., Taylor, J. A., Iwamoto, G. A., et al. 2000. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci U S A, 97, 12729-34.
Hirosumi, J., Tuncman, G., Chang, L., et al. 2002. A central role for JNK in obesity and insulin resistance. Nature, 420, 333-6.
Horton, J. D., Goldstein, J. L. & Brown, M. S. 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest, 109, 1125-31.
Hosogai, N., Fukuhara, A., Oshima, K., et al. 2007. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes, 56, 901-11.
Hotta, K., Funahashi, T., Arita, Y., et al. 2000. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol, 20, 1595-9.
Hu, W., Li, L., Yang, M., et al. 2013. Circulating Sfrp5 is a signature of obesity-related metabolic disorders and is regulated by glucose and liraglutide in humans. J Clin Endocrinol Metab, 98, 290-8.
Jiang, C., Qu, A., Matsubara, T., et al. 2011. Disruption of hypoxia-inducible factor 1 in adipocytes improves insulin sensitivity and decreases adiposity in high-fat diet-fed mice. Diabetes, 60, 2484-95.
Kalu, D. N. 1991. The ovariectomized rat model of postmenopausal bone loss. Bone Miner, 15, 175-91.
Kanda, H., Tateya, S., Tamori, Y., et al. 2006. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest, 116, 1494-505.
Kawano, Y. & Cohen, D. E. 2013. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol, 48, 434-41.
Kennell, J. A. & Macdougald, O. A. 2005. Wnt signaling inhibits adipogenesis through beta-catenin-dependent and -independent mechanisms. J Biol Chem, 280, 24004-10.
Kim, S., Shin, H. J., Kim, S. Y., et al. 2004. Genistein enhances expression of genes involved in fatty acid catabolism through activation of PPARalpha. Mol Cell Endocrinol, 220, 51-8.
Kuiper, G. G., Lemmen, J. G., Carlsson, B., et al. 1998. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology, 139, 4252-63.
Kumagai, S., Holmang, A. & Bjorntorp, P. 1993. The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol Scand, 149, 91-7.
Lasco, A., Gaudio, A., Morabito, N., et al. 2004. Effects of a long-term treatment with raloxifene on insulin sensitivity in postmenopausal women. Diabetologia, 47, 571-574.
Laudes, M. 2011. Role of WNT signalling in the determination of human mesenchymal stem cells into preadipocytes. J Mol Endocrinol, 46, R65-72.
Law, J., Bloor, I., Budge, H., et al. 2014. The influence of sex steroids on adipose tissue growth and function. Horm Mol Biol Clin Investig, 19, 13-24.
Lee, Y. M., Choi, J. S., Kim, M. H., et al. 2006. Effects of dietary genistein on hepatic lipid metabolism and mitochondrial function in mice fed high-fat diets. Nutrition, 22, 956-64.
Lizcano, F. & Guzman, G. 2014. Estrogen Deficiency and the Origin of Obesity during Menopause. Biomed Res Int, 2014, 757461.
Logan, C. Y. & Nusse, R. 2004. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol, 20, 781-810.
Lolmede, K., Durand De Saint Front, V., Galitzky, J., et al. 2003. Effects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obes Relat Metab Disord, 27, 1187-95.
Longo, K. A., Wright, W. S., Kang, S., et al. 2004. Wnt10b inhibits development of white and brown adipose tissues. J Biol Chem, 279, 35503-9.
Lorenzo, M., Fernández-Veledo, S., Vila-Bedmar, R., et al. 2008. Insulin resistance induced by tumor necrosis factor-α in myocytes and brown adipocytes. 86, E94-E104.
Lovejoy, J. C., Champagne, C. M., De Jonge, L., et al. 2008. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes (Lond), 32, 949-58.
Martinez De Morentin, P. B., Gonzalez-Garcia, I., Martins, L., et al. 2014. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab, 20, 41-53.
Mauvais-Jarvis, F., Clegg, D. J. & Hevener, A. L. 2013. The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev, 34, 309-38.
Mcardle, M. A., Finucane, O. M., Connaughton, R. M., et al. 2013. Mechanisms of obesity-induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies. Front Endocrinol (Lausanne), 4, 52.
Meli, R., Pacilio, M., Raso, G. M., et al. 2004. Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats. Endocrinology, 145, 3115-21.
Melnikova, I. & Wages, D. 2006. Anti-obesity therapies. Nat Rev Drug Discov, 5, 369-70.
Miyazawa-Hoshimoto, S., Takahashi, K., Bujo, H., et al. 2003. Elevated serum vascular endothelial growth factor is associated with visceral fat accumulation in human obese subjects. Diabetologia, 46, 1483-8.
Montague, C. T. & O'rahilly, S. 2000. The perils of portliness: causes and consequences of visceral adiposity. Diabetes, 49, 883-8.
Naaz, A., Yellayi, S., Zakroczymski, M. A., et al. 2003. The soy isoflavone genistein decreases adipose deposition in mice. Endocrinology, 144, 3315-20.
Nogowski, L., Mackowiak, P., Kandulska, K., et al. 1998. Genistein-induced changes in lipid metabolism of ovariectomized rats. Ann Nutr Metab, 42, 360-6.
Ntambi, J. M. & Young-Cheul, K. 2000. Adipocyte differentiation and gene expression. J Nutr, 130, 3122s-3126s.
Okla, M., Zaher, W., Alfayez, M., et al. 2018. Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1beta on White Adipocyte Browning. Inflammation, 41, 626-642.
Ouchi, N., Higuchi, A., Ohashi, K., et al. 2010. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science, 329, 454-7.
Palacios-Gonzalez, B., Zarain-Herzberg, A., Flores-Galicia, I., et al. 2014. Genistein stimulates fatty acid oxidation in a leptin receptor-independent manner through the JAK2-mediated phosphorylation and activation of AMPK in skeletal muscle. Biochim Biophys Acta, 1841, 132-40.
Pedersen, S. B., Bruun, J. M., Kristensen, K., et al. 2001. Regulation of UCP1, UCP2, and UCP3 mRNA expression in brown adipose tissue, white adipose tissue, and skeletal muscle in rats by estrogen. Biochem Biophys Res Commun, 288, 191-7.
Pellegrinelli, V., Rouault, C., Rodriguez-Cuenca, S., et al. 2015. Human Adipocytes Induce Inflammation and Atrophy in Muscle Cells During Obesity. Diabetes, 64, 3121-34.
Perakakis, N., Triantafyllou, G. A., Fernandez-Real, J. M., et al. 2017. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol, 13, 324-337.
Pfeilschifter, J., Köditz, R., Pfohl, M., et al. 2002. Changes in proinflammatory cytokine activity after menopause. Endocr Rev, 23, 90-119.
Queipo-Ortuño, M. I., Escoté, X., Ceperuelo-Mallafré, V., et al. 2012. FABP4 dynamics in obesity: discrepancies in adipose tissue and liver expression regarding circulating plasma levels. PLoS One, 7, e48605.
Rattner, A., Hsieh, J. C., Smallwood, P. M., et al. 1997. A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. Proc Natl Acad Sci U S A, 94, 2859-63.
Ribas, V., Nguyen, M. T., Henstridge, D. C., et al. 2010. Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice. Am J Physiol Endocrinol Metab, 298, E304-19.
Rius, J., Guma, M., Schachtrup, C., et al. 2008. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature, 453, 807-11.
Rodriguez, A., Ezquerro, S., Mendez-Gimenez, L., et al. 2015. Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism. Am J Physiol Endocrinol Metab, 309, E691-714.
Rogers, N. H., Perfield, J. W., 2nd, Strissel, K. J., et al. 2009. Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology, 150, 2161-8.
Ropero, A. B., Alonso-Magdalena, P., Quesada, I., et al. 2008. The role of estrogen receptors in the control of energy and glucose homeostasis. Steroids, 73, 874-9.
Rosen, E. D. & Macdougald, O. A. 2006. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol, 7, 885-96.
Ross, S. E., Hemati, N., Longo, K. A., et al. 2000. Inhibition of adipogenesis by Wnt signaling. Science, 289, 950-3.
Sakamoto, T., Takahashi, N., Sawaragi, Y., et al. 2013. Inflammation induced by RAW macrophages suppresses UCP1 mRNA induction via ERK activation in 10T1/2 adipocytes. Am J Physiol Cell Physiol, 304, C729-38.
Saponaro, C., Gaggini, M., Carli, F., et al. 2015. The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis. Nutrients, 7, 9453-74.
Sato, M., Rippy, M. K. & Bryant, H. U. 1996. Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. Faseb j, 10, 905-12.
Seli, E., Pehlivan, T., Selam, B., et al. 2002. Estradiol down-regulates MCP-1 expression in human coronary artery endothelial cells. Fertil Steril, 77, 542-7.
Shen, M., Kumar, S. P. & Shi, H. 2014. Estradiol regulates insulin signaling and inflammation in adipose tissue. Horm Mol Biol Clin Investig, 17, 99-107.
Shimano, H. & Sato, R. 2017. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat Rev Endocrinol, 13, 710-730.
Solum, D. T. & Handa, R. J. 2002. Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus. J Neurosci, 22, 2650-9.
Stumvoll, M., Goldstein, B. J. & Van Haeften, T. W. 2005. Type 2 diabetes: principles of pathogenesis and therapy. Lancet, 365, 1333-46.
Szkudelska, K., Nogowski, L. & Szkudelski, T. 2000. Genistein affects lipogenesis and lipolysis in isolated rat adipocytes. J Steroid Biochem Mol Biol, 75, 265-71.
Takeda, K., Toda, K., Saibara, T., et al. 2003. Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol, 176, 237-46.
Tang, C., Zhang, K., Zhao, Q., et al. 2015. Effects of Dietary Genistein on Plasma and Liver Lipids, Hepatic Gene Expression, and Plasma Metabolic Profiles of Hamsters with Diet-Induced Hyperlipidemia. J Agric Food Chem, 63, 7929-36.
Tchernof, A., Calles-Escandon, J., Sites, C. K., et al. 1998. Menopause, central body fatness, and insulin resistance: effects of hormone-replacement therapy. Coron Artery Dis, 9, 503-11.
Tchernof, A. & Poehlman, E. T. 1998. Effects of the menopause transition on body fatness and body fat distribution. Obes Res, 6, 246-54.
Tontonoz, P. & Spiegelman, B. M. 2008. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem, 77, 289-312.
Torres, M. J., Kew, K. A., Ryan, T. E., et al. 2018. 17beta-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle. Cell Metab, 27, 167-179.e7.
Toth, M. J., Poehlman, E. T., Matthews, D. E., et al. 2001. Effects of estradiol and progesterone on body composition, protein synthesis, and lipoprotein lipase in rats. Am J Physiol Endocrinol Metab, 280, E496-501.
Toth, M. J., Tchernof, A., Sites, C. K., et al. 2000. Menopause-related changes in body fat distribution. Ann N Y Acad Sci, 904, 502-6.
Trayhurn, P. 2013. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev, 93, 1-21.
Trayhurn, P. & Wood, I. S. 2004. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr, 92, 347-55.
Tremollieres, F. A., Pouilles, J. M. & Ribot, C. A. 1996. Relative influence of age and menopause on total and regional body composition changes in postmenopausal women. Am J Obstet Gynecol, 175, 1594-600.
Van Heek, M., Compton, D. S., France, C. F., et al. 1997. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest, 99, 385-90.
Van Leeuwen, F. E., Benraadt, J., Coebergh, J. W., et al. 1994. Risk of endometrial cancer after tamoxifen treatment of breast cancer. Lancet, 343, 448-52.
Weigt, C., Hertrampf, T., Flenker, U., et al. 2015. Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats. J Steroid Biochem Mol Biol, 154, 12-22.
Weigt, C., Hertrampf, T., Zoth, N., et al. 2012. Impact of estradiol, ER subtype specific agonists and genistein on energy homeostasis in a rat model of nutrition induced obesity. Mol Cell Endocrinol, 351, 227-38.
Wellen, K. E. & Hotamisligil, G. S. 2003. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest, 112, 1785-8.
Wu, J., Bostrom, P., Sparks, L. M., et al. 2012. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell, 150, 366-76.
Wu, Z., Rosen, E. D., Brun, R., et al. 1999. Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell, 3, 151-8.
Xiang, L., Xiang, G., Yue, L., et al. 2014. Circulating irisin levels are positively associated with endothelium-dependent vasodilation in newly diagnosed type 2 diabetic patients without clinical angiopathy. Atherosclerosis, 235, 328-33.
Xu, B., Lovre, D. & Mauvais-Jarvis, F. 2016. Effect of selective estrogen receptor modulators on metabolic homeostasis. Biochimie, 124, 92-7.
Yada-Hashimoto, N., Nishio, Y., Ohmichi, M., et al. 2006. Estrogen and raloxifene inhibit the monocytic chemoattractant protein-1-induced migration of human monocytic cells via nongenomic estrogen receptor alpha. Menopause, 13, 935-41.
Yasui, T., Uemura, H., Hyodo, S., et al. 2009. Raloxifene reduces circulating levels of interleukin-7 and monocyte chemoattractant protein-1 in postmenopausal women. Atherosclerosis, 204, 471-5.
Yoo, N. Y., Jeon, S., Nam, Y., et al. 2015. Dietary Supplementation of Genistein Alleviates Liver Inflammation and Fibrosis Mediated by a Methionine-Choline-Deficient Diet in db/db Mice. J Agric Food Chem, 63, 4305-11.
You, T., Ryan, A. S. & Nicklas, B. J. 2004. The metabolic syndrome in obese postmenopausal women: relationship to body composition, visceral fat, and inflammation. J Clin Endocrinol Metab, 89, 5517-22.
Zhang, Y., Xie, C., Wang, H., et al. 2016. Irisin exerts dual effects on browning and adipogenesis of human white adipocytes. Am J Physiol Endocrinol Metab, 311, E530-41.


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