title: Molecular effects of ER alpha- and beta-selective agonists on regulation of energy homeostasis in obese female Wistar rats.
abstract: The molecular mechanisms underlying the effects of selective ER subtype activation on lipogenesis, adipogenesis, lipid utilization and storage as well as glucose metabolism are currently largely unknown and were analyzed in female OVX Wistar rats on a high-fat diet. Rats received estradiol (E2), ER subtype-selective agonists (Alpha and Beta), and genistein (Gen) for 10 weeks. In adipose tissue, treatment with E2, Alpha, and Beta significantly decreased lipogenic (SREBP-1c, FAS) and adipogenic genes (LPL, PPAR gamma). In liver and skeletal muscle of E2-, Alpha-, Beta-, and Gen-treated animals, lipogenesis and triglyceride accumulation were significantly reduced. Increased hepatic and muscular PPAR gamma mRNA expression was observed in untreated, Beta- and Gen-treated animals, which correlates with increased hepatic glucose uptake. However, only untreated animals showed impaired insulin sensitivity compared to all other groups. Therefore, PPAR gamma up-regulation in untreated animals suggests a compensatory mechanism, probably due to increased triglyceride accumulation in non-adipose tissues. Beta- and Gen-treated animals may benefit from the anabolic potency of ER beta that ameliorates lipid and glucose utilization in muscle. Activation of either ER subtype reduces fat enrichment and improves insulin sensitivity. Depending on the investigated tissue, different molecular pathways seem to be involved.
authors.affiliation: German Sports University Cologne, Institute of Cardiovascular Research and Sports Medicine, Department of Cellular and Molecular Sports Medicine, Am Sportpark Müngersdorf 6, 50933 Köln, Germany. c.weigt@dshs-koeln.de.
authors.forename: Carmen
authors.initials: C
authors.lastname: Weigt
authors.forename: Torsten
authors.initials: T
authors.lastname: Hertrampf
authors.forename: Felix M
authors.initials: FM
authors.lastname: Kluxen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flenker
authors.forename: Frank
authors.initials: F
authors.lastname: Hülsemann
authors.forename: Karl Heinrich
authors.initials: KH
authors.lastname: Fritzemeier
authors.forename: Patrick
authors.initials: P
authors.lastname: Diel
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007553:Isotope Labeling; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C491898:Fas protein, rat; D007328:Insulin; D047495:PPAR gamma; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D019014:fas Receptor; D004958:Estradiol; D019833:Genistein; D008071:Lipoprotein Lipase
keywords: 17β-estradiol; Alpha; BMI; Beta; E2; ER; ER alpha-selective agonist 16α-LE2; ER beta-selective agonist 8β-VE2; Estrogen receptor subtype-selective agonist; FAS; Gen; Genistein; Glucose uptake; Glut4; HF; HOMA; Homeostasis Assessment Model; IRMS; Isotope-ratio mass spectrometry; LDL; LF; LME; Lipid metabolism; Lipogenesis; OVX; Obesity; PPAR; PPAR responsive element; PPRE; SREBP-1c; T2DM; TC; TG; VLDL; VPDB; Vienna Pee Dee Belemnite; body mass index; estrogen receptor; fatty acid synthase; genistein; glucose transporter 4; high fat; linear mixed effects; low fat; low-density lipoprotein cholesterol; ovariectomized; peroxisome proliferator-activated receptor; sterol regulatory element binding protein 1c; total cholesterol; triglyceride; type 2 diabetes mellitus; very-low-density lipoprotein cholesterol