title: Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats.
abstract: The leptin resistant Zucker diabetic fatty (ZDF) rats are hyperphagic and become obese, but whereas the males develop type 2 diabetes mellitus (T2DM), the females remain euglycaemic. As estrogen deficiency is known to increase the risk of developing T2DM, we evaluated the role of ER subtypes alpha and beta in the development of glucose tolerance in leptin resistant ovariectomized (OVX) ZDF rats. At least six rats per group were treated with either vehicle (OVX), 17β-estradiol (E2), ER subtype-selective agonists (Alpha and Beta), or genistein (Gen) for 17 weeks. At the end of the treatment period a glucose tolerance assay was performed and the metabolic flux of (13)C-glucose for the E2 group was investigated. OVX ZDF rats treated with E2, Alpha, Beta, and Gen tolerated the glucose significantly better than untreated controls. E2 treatment increased absorbance/flux of (13)C-glucose to metabolic relevant tissues such liver, adipose tissue, gastrocnemius, and soleus muscle. Moreover, whereas Alpha treatment markedly increased mRNA expression of GLUT4 in gastrocnemius muscle, Beta treatment resulted in the largest fiber sizes of the soleus muscle. Treatment with Gen increased both the mRNA expression of GLUT 4 and the fiber sizes in the skeletal muscle. In addition, E2 and Alpha treatment decreased food intake and body weight gain. In summary, estrogen-improved glucose absorption is mediated via different molecular mechanisms: while activation of ER alpha seems to stimulate muscular GLUT4 functionality, activation of ER beta results in a hypertrophy of muscle fibers. In addition, selective activation of ER alpha decreased food intake and body weight gain. Our data further indicate that ER subtype-selective agonists and genistein improve systemic glucose tolerance also in the absence of a functional leptin signaling pathway.
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. Electronic address: c.weigt@web.de.
authors.forename: Carmen
authors.initials: C
authors.lastname: Weigt
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. Electronic address: torsten.hertrampf@grunenthal.com.
authors.forename: Torsten
authors.initials: T
authors.lastname: Hertrampf
authors.affiliation: German Sports University Cologne, Institute of Biochemistry, Am Sportpark Müngersdorf 6, 50933 Köln, Germany. Electronic address: u.flenker@biochem.dshs-koeln.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Flenker
authors.affiliation: German Sports University Cologne, Institute of Biochemistry, Am Sportpark Müngersdorf 6, 50933 Köln, Germany. Electronic address: f.huelsemann@biochem.dshs-koeln.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Hülsemann
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. Electronic address: pkurnaz@uni-bonn.de.
authors.forename: Pinar
authors.initials: P
authors.lastname: Kurnaz
authors.affiliation: University of Essen-Duisburg, Universitätsstraße 2, 45141 Essen, Germany. Electronic address: heiner.fritzemeier@uni-due.de.
authors.forename: Karl Heinrich
authors.initials: KH
authors.lastname: Fritzemeier
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. Electronic address: Diel@dshs-koeln.de.
authors.forename: Patrick
authors.initials: P
authors.lastname: Diel
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D020738:Leptin / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D011960:Receptors, Estrogen / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects
chemical_list: D051275:Glucose Transporter Type 4; D020738:Leptin; D011960:Receptors, Estrogen; C495694:Slc2a4 protein, rat; D004958:Estradiol; D019833:Genistein; D005947:Glucose
keywords: Estrogen receptor subtype-selective agonists; Genistein; Glucose metabolism; Leptin; Obesity; ZDF rats