TranslationalEstrogen receptor protein content is different in abdominal than gluteal subcutaneous 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.
References (52)
- et al.
Contribution of visceral fat mass to the insulin resistance of aging
Metabolism
(1995) - et al.
Relative contribution of obesity and body fat distribution to alterations in glucose insulin homeostasis: predictive values of selected indices in premenopausal women
Am J Clin Nutr
(1989) Sexual dimorphism of body composition
Best Pract Res Clin Endocrinol Metab
(2007)- et al.
Regional fat distribution in women and risk of cardiovascular disease
Am J Clin Nutr
(1997) - et al.
Contributions of regional adipose tissue depots to plasma lipoprotein concentrations in overweight men and women: possible protective effects of thigh fat
Metabolism
(1991) - et al.
Waist and hip circumferences have independent and opposite effects on cardiovascular disease risk factors: the Quebec family study
Am J Clin Nutr
(2001) - et al.
Demonstration of estrogen receptor subtypes alpha and beta in human adipose tissue: influences of adipose cell differentiation and fat depot localization
Mol Cell Endocrinol
(2001) - et al.
Identification of estrogen receptor beta rna in human breast and abdominal subcutaneous adipose tissue
Biochem Biophys Res Commun
(1998) - et al.
The ratio of estrogen receptor alpha to estrogen receptor beta in adipose tissue is associated with leptin production and obesity
Steroids
(2007) - et al.
Visceral adipose-tissue differences in black-and-white women
Am J Clin Nutr
(1995)
Abdominal fat distribution and metabolic risk factors: effects of race
Metabolism
Racial differences in amounts of visceral adipose tissue in young adults: the CARDIA (Coronary Artery Risk Development In Young Adults) Study
Am J Clin Nutr
Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice
Biochem Biophys Res Commun
Interaction between menopausal status and obesity in affecting breast cancer risk
Maturitas
Regional adiposity and morbidity
Physiol Rev
Insulin resistance in aging is related to abdominal obesity
Diabetes
Adiposity, fat distribution, and cardiovascular risk
Ann Intern Med
La differenciation sexuelle: Facteur determinant des formes: De l'obesite
Presse Med
Gluteofemoral body fat as a determinant of metabolic health
Int J Obes (Lond)
Fat cell metabolism in different regions in women. Effect of menstrual cycle, pregnancy, and lactation
J Clin Invest
Does oestrogen allow women to store fat more efficiently? A biological advantage for fertility and gestation
Obes Rev
Efficient fat storage in premenopausal women and in early pregnancy: a role for estrogen
J Clin Endocrinol Metab
Contributions of total and regional fat mass to risk for cardiovascular disease in older women
Am J Physiol Endocrinol Metab
Body compartment and subcutaneous adipose tissue distribution—risk factor patterns in obese subjects
Obes Res
Fat distribution, physical activity, and cardiovascular risk factors
Med Sci Sports Exerc
Body fat distribution, the menopause transition, and hormone replacement therapy
Diabetes Metab
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Disclosure Summary: The authors have nothing to disclose.