Elsevier

Metabolism

Volume 62, Issue 8, August 2013, Pages 1180-1188
Metabolism

Translational
Estrogen receptor protein content is different in abdominal than gluteal subcutaneous adipose tissue of overweight-to-obese premenopausal women

https://doi.org/10.1016/j.metabol.2013.02.010Get rights and content

Abstract

Objective

Premenopausal women demonstrate a distinctive gynoid body fat distribution and circulating estrogen status is associated with the maintenance of this adiposity patterning. Estrogen's role in modulation of regional adiposity may occur through estrogen receptors (ERs), which are present in human adipose tissue. The purpose of this study was to determine regional differences in the protein content of ERα, ERβ, and the G protein-coupled estrogen receptor (GPER) between the abdominal (AB) and gluteal (GL) subcutaneous adipose tissue of overweight-to-obese premenopausal women.

Materials/Methods

Biopsies of the subcutaneous AB and GL adipose tissue were performed in 15 premenopausal women (7 Caucasian/8 African American, 25.1 ± 1.8 years, BMI 29.5 ± 0.5 kg/m2). Adipose tissue protein content was measured by western blot analysis and correlation analyses were conducted to assess the relationship between ER protein content and anthropometric indices/body composition measurements.

Results

We found that ERα protein was higher in AB than GL (AB 1.0 ± 0.2 vs GL 0.67 ± 0.1 arbitrary units [AU], P = 0.02), ERβ protein was higher in GL than AB (AB 0.78 ± 0.12 vs GL 1.3 ± 0.2 AU, P = 0.002), ERα/ERβ ratio was higher in AB than GL (AB 1.9 ± 0.4 vs GL 0.58 ± 0.08 AU, P = 0.007), and GPER protein content was similar in AB and GL (P = 0.80) subcutaneous adipose tissue. Waist-to-hip ratio was inversely related to gluteal ERβ (r2 = 0.315, P = 0.03) and positively related to gluteal ERα/ERβ ratio (r2 = 0.406, P = 0.01).

Conclusions

These results indicate that depot specific ER content may be an important underlying determinant of regional effects of estrogen in upper and lower body adipose tissue of overweight-to-obese premenopausal women.

Introduction

Excess weight increases the risk of multiple disease states, including heart disease, hypertension, Type 2 diabetes, certain cancers (e.g. colon and breast) and stroke [1], [2], [3], [4]. Recent body composition studies emphasize the importance of regional adiposity compared to overall adiposity in assessing disease risk [1], [2], [3], [4], [5]. The hypothesis that the localization of body fat, and not merely total fat mass, holds high importance in the elevated health risks associated with obesity is not a new idea; J. Vague first suggested that the relative amount of upper- versus lower-body obesity was important [6].

Premenopausal women demonstrate a distinctive gluteal–femoral body fat distribution [7], [8], [9]. Although evolutionary reasoning behind this pattern of adiposity is not definitive, one hypothesis is that women accumulate energy reserves in the lower body in preparation for increased energy utilization and adipose mobilization from this depot during pregnancy and lactation [10], [11], [12]. Sequestration of fat in the lower body region is associated with decreased risk for cardiovascular and metabolic disease versus accumulation of central adiposity [9], [13], [14], [15], [16], [17]. Therefore, a full understanding of the physiology behind why, and by what mechanisms, adipose tissue accumulates in specific depots is important in efforts of obesity and chronic disease prevention.

Estrogen status is related to the maintenance of a gynoid body fat distribution [18]. The loss of circulating estrogen over the menopausal transition is associated with increases in central adiposity, a pattern of adiposity linked to increased cardio-metabolic disease risk [19], [20], [21], [22]. The expression of estrogen receptor alpha (ERα) [23], [24], estrogen receptor beta (ERβ) [25], [26], [27], [28], and the G protein-coupled estrogen receptor (GPER) [29] within human adipose tissue indicates estrogen has direct effects within adipose tissue [30]. Taken together, a shift toward increased central adiposity with decreases in circulating estrogen status and the presence of ERs within the adipose tissue present a strong case for modulation of adipose accumulation via estrogen, potentially in a region specific manner.

There have been few investigations into regional differences in estrogen receptor expression in human adipose tissue, with most of those focusing on differences in estrogen receptor gene expression between subcutaneous and visceral abdominal adipose tissue [28], [31]. To our knowledge studies are lacking which characterize the protein content of all three estrogen receptors in upper and lower body adipose tissue in overweight or moderately obese women. There is limited evidence that ERβ mRNA expression is higher in gluteal than abdominal subcutaneous adipose tissue (SAT) from overweight premenopausal women [25], supporting the hypothesis that regional differences in ER expression may be a mechanism behind regional differences in adipose accumulation and/or mobilization. Importantly, ERα and ERβ are reported to have distinct actions and ERβ may even oppose the actions of ERα [25], [28], [32], [33], highlighting the need for a clear representation of the relative ERα to ERβ ratio in each adipose depot. Therefore, the primary purpose of this study was to determine if there are regional differences in the protein content of ERα, ERβ, and GPER between the abdominal (AB) and gluteal (GL) SAT of overweight-to-obese premenopausal women demonstrating a gluteal–femoral body fat distribution (defined as a waist-to-hip ratio < 0.85).

African American women tend to be more obese than Caucasian women [34] and for a given amount of total body adiposity Caucasian and African American women are reported to have different body fat distributions. African American women have less visceral adipose tissue for a similar age and BMI [35], [36], [37], and/or have greater amounts of SAT even after adjustment for total body fat [36], [38], [39]. If these racial differences in regional adiposity are related to local adipose tissue actions of estrogens is unknown. Therefore, as a secondary aim, subgroup analyses were conducted to investigate racial (Caucasian and African American) differences in regional ER protein content. Establishing regional SAT ER protein content is an important step towards understanding how estrogen may affect adipose depots in the upper and lower body differently, potentially playing a modulatory role in regional adipose tissue accumulation.

Section snippets

Participants

Fifteen overweight/obese premenopausal women, (7 Caucasian/8 African American, 25.1 ± 1.8 years, 81.3 ± 2.5 kg, BMI 29.5 ± 0.5 kg/m2) between 18 and 39 years old were studied (Table 1). Participants were eumenorrheic (average cycle length 30 ± 1 days), not taking hormonal contraceptives (no use in  6 months at study entry), weight stable (< 3 kg weight change in previous 6 months) and not regularly active (< 30 min/day of exercise, < 2 days/week). Exclusion criteria included: trying to get pregnant, currently

Results

Baseline characteristics of the participants in the study are included in Table 1 and circulating sex hormone levels within one day of the biopsy in Table 2. African American women had elevated android fat mass compared to Caucasian women; all other participant characteristics were similar between the racial subgroups. There were no group differences in circulating sex hormones.

Fig. 1 presents evidence of correct band detection for ERα, ERβ, and GPER. Positive control lysate samples and

Discussion

This is the first study to characterize protein content of the three known estrogen receptors, ERα, ERβ, and GPER, in abdominal and gluteal subcutaneous adipose tissue samples from Caucasian and African American premenopausal women. Importantly, we found estrogen receptors had depot specific protein content patterns, in agreement with previously reported mRNA results [25]. Abdominal SAT contained more ERα protein compared to gluteal, and gluteal SAT contained more ERβ protein when compared to

Conclusions

The novel results from the current study demonstrate clear differences in ERα and ERβ protein content in the abdominal and gluteal subcutaneous adipose tissue of overweight-to-obese premenopausal women. The presence of all three ER subtypes as well as increased ERα content in the abdominal, and increased ERβ content in the gluteal, subcutaneous adipose tissue suggests that ERα and ERβ may both play a role in modulating regional adiposity, and thereby also the cardiometabolic disease risk

Author contributions

KMG developed the research question, performed all study related duties including participant recruitment, scheduling, sample collection and processing, western blots, statistical analysis, data interpretation and manuscript writing. EEC assisted with all sample collections, western blots, and took part in manuscript writing and editing. RCH assisted with development of the research question, performed all adipose tissue biopsies, and assisted with interpretation of data and writing of the

Funding

This research was supported by an ACSM Foundation Research Grant from the American College of Sports Medicine Foundation.

Conflict of interest

The authors have no conflicts of interest in regard to the contents of this paper.

Acknowledgments

The authors would like to thank Joseph Pierce for his assistance with sample preparation, Jacques Robidoux for his technical guidance, Pamila Allen at the University of Colorado Denver CTRC Core laboratory for conducting some of the serum sex hormone assays, and the participants who took part in the research study.

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