Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats. Issue 154 (November 2015)

• Record Type: Journal Article
• Authors: Weigt, Carmen; Hertrampf, Torsten; Flenker, Ulrich; Hülsemann, Frank; Kurnaz, Pinar; Fritzemeier, Karl Heinrich; Diel, Patrick
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 154(2015)
• Page Start: 12
• Page End: 22
• Publication Date: 2015-11
• Subjects: αERKO estrogen receptor alpha knockout -- AgRP agouti-related protein -- AlphaER alpha-selective agonist 16α-LE2 -- BetaER beta-selective agonist 8β-VE2 -- βERKO estrogen receptor beta knockout -- BSA bovine serum albumin -- b. wt. body weight -- CART cocaine- and amphetamine-regulated transcript -- DAB 3, 3′-diaminobenzidine-tetrahydrochloride -- E2 17β-estradiol -- ER estrogen receptor -- ERKO estrogen receptor knockout -- fa/fa fatty/fatty -- Gen genistein -- GLUT4 glucose transporter 4 -- HSD honestly significant difference -- IRMS isotope-ratio mass spectrometry -- LME linear mixed effects -- NPY neuropeptid Y -- OVX ovariectomized -- POMC proopiomelanocortin -- PPAR peroxisome proliferator-activated receptor -- RT-PCR reverse transcriptase-polymerase chain reaction -- T2DM type 2 diabetes mellitus -- TBS tris-buffered saline -- VPDB Vienna Pee Dee Belemnite -- ZDF Zucker diabetic fatty; Estrogen receptor subtype-selective agonists -- Obesity -- ZDF rats -- Leptin -- Glucose metabolism -- Genistein; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2015.06.002
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Activation of ER alpha reduced body weight gain in leptin resistant female ZDF rats. The ER alpha mediated lower food intake independent of leptin signaling. Activation of both ER subtypes improved systemic glucose tolerance. In skeletal muscle, stimulation of ER alpha increased GLUT4 expression. Activation of ER beta induced hypertrophy of skeletal muscle fibers. 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.