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Randomized Controlled Trial
. 2017 May 4;12(5):e0176446.
doi: 10.1371/journal.pone.0176446. eCollection 2017.

Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor α and β in postmenopausal women

Young-Min Park  1 , Rocio I Pereira  2   3 , Christopher B Erickson  1 , Tracy A Swibas  1 , Kimberly A Cox-York  4 , Rachael E Van Pelt  1   5
Affiliations
Randomized Controlled Trial

Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor α and β in postmenopausal women

Young-Min Park et al. PLoS One. .

Abstract

We recently demonstrated that short-term estradiol (E2) treatment improved insulin-mediated suppression of lipolysis in postmenopausal women, but to a greater extent in those who were late compared to early postmenopausal. In this follow-up study we tested whether subcutaneous adipose tissue (SAT) expression of estrogen receptors (ER) α and β differs between early and late postmenopausal women. We further tested whether the balance of ERα to ERβ in SAT determined the effect of E2 on SAT insulin sensitivity. The present study included 35 women who were ≤6 years past menopause (EPM; n = 16) or ≥10 years past menopause (LPM; n = 19). Fasted SAT samples were taken following 1-week transdermal E2 treatment or placebo (PL) in a random cross-over design. Samples were analyzed for nuclear/cytosolic protein content and mRNA expression using Western blot and qPCR, respectively. While ESR1 increased slightly (~1.4-fold) following E2 treatment in both groups, ERα and ERβ protein expression did not differ between groups at baseline or in response to E2. However, the balance of ERα/ERβ protein in the SAT nuclear fraction increased 10% in EPM compared to a 25% decrease in LPM women (group x treatment interaction, p<0.05). A greater proportion of ERα/ERβ protein in the nuclear fraction of SAT at baseline (placebo day) was associated with greater reduction in SAT insulin resistance (i.e., better suppression of lipolysis, EC50) in response to E2 (r = -0.431, p<0.05). In conclusion, there do not appear to be differences in the proportion of adipose tissue ERα/ERβ protein in late, compared to early, postmenopausal women. However, the balance of ERα/ERβ may be important for E2-mediated improvement in adipose tissue insulin sensitivity.

Trial registration: Clinical Trials#: NCT01605071.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Evidence of correct western band detection for estrogen receptors (ER), the purity of nuclear fraction, and representative images.
(A) ERα and β protein bands in nuclear and cytosolic fraction, Lane .1: positive control (MCF7), Lane 2: negative control (MDA-MB-231) or empty well (loading buffer only), Lane 3: 30ug protein from adipose tissue; (B) the purity of nuclear fraction, Lane 1: nuclear fraction, Lane 2: cytosolic fraction. αTubulin was used as a cytosolic marker; no bands were detected in nuclear fraction; (C) representative images of ERα and β protein bands in nuclear and cytosolic fraction.
Fig 2
Fig 2. Adipocyte size and distribution.
(A) Representative images of isolated adipocytes each group; (B) the proportion of small (20–60μ), medium (60–100μ), and large (100–140μ) adipocytes; and the average diameter of whole adipocytes. Values are means±SE; early postmenopausal women [EPM; n = 16]; late postmenopausal women [LPM; n = 17]; treated either with placebo [PL] or estradiol [E2].
Fig 3
Fig 3. Estrogen receptor (ER) gene expression.
(A) Baseline (placebo) group difference for ESR1 (ERα) and ESR2 (ERβ) gene expression; (B) fold-change from placebo condition in response to 1 week of transdermal E2 treatment. Values are means±SE; early postmenopausal women [EPM; n = 12]; late postmenopausal women [LPM; n = 16].
Fig 4
Fig 4. Estrogen receptor (ER) protein content.
(A) ERα protein in nuclear fraction, (B) ERα protein in cytosolic fraction, (C) ERβ protein in nuclear fraction, (D) ERβ protein in cytosolic fraction, (E) ratio of ERα/ERβ protein in nuclear fraction, and (F) ratio of ERα/ERβ protein in cytosolic fraction. Values are means±SE (n = 14–19 per group). NS = no significant difference between groups; Interaction = group-by-treatment interaction; group (early postmenopausal women [EPM] vs. late postmenopausal women [LPM]); treatment (estradiol [E2] vs. placebo [PL]). *Denotes significant (P<0.05) within group change in response to E2 treatment
Fig 5
Fig 5. Estradiol (E2)-mediated change in adipose tissue insulin resistance versus the ratio of estrogen receptor (ER) α/β protein.
Association between E2-mediated change in adipose tissue insulin resistance (ΔEC50) and baseline (placebo): (A) nuclear ERα/ERβ; or (B) cytosolic ERα/ERβ. †Denotes a significant (P<0.05) correlation.
See this image and copyright information in PMC

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