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Role of Estrogen and Its Receptors in Adipose Tissue Glucose Metabolism in Pre- and Postmenopausal Women
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0002-3678-1799
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0002-5627-8904
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.ORCID iD: 0000-0002-7920-8909
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2022 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 107, no 5, p. E1879-E1889Article in journal (Refereed) Published
Abstract [en]

Context: Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance and type 2 diabetes; however, the cellular mechanisms are not well understood.

Objective: This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes.

Methods: Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 years old, respectively) were used to measure gene expression of ESR1 and ESR2. SAT tissue was incubated with E2, and glucose uptake and estrogen receptor levels were measured. Polymorphisms in ESR1 and ESR2 were addressed in public databases to identify single nucleotide polymorphisms associated with metabolic traits.

Results: ESR2 expression was lower in pre- vs postmenopausal women, corresponding to lower ESR1:ESR2 gene expression ratio in postmenopausal women. In premenopausal women, the expression of ESR1 was higher in VAT than in SAT. In both pre- and postmenopausal women, ESR2 expression was lower in VAT than in SAT. In late, but not pre- or early postmenopausal women, E2 reduced glucose uptake and GLUT4 protein and increased expression of ESR2. ESR1 polymorphisms were associated with weight, body fat distribution, and total cholesterol, and ESR2 polymorphisms were associated with total cholesterol and triglyceride levels and with body fat percentage.

Conclusion: E2 inhibits glucose utilization in human adipocytes in late postmenopausal women. Changes in glucose utilization over time since menopause may be explained by a lower ESR1:ESR2 ratio. This can have clinical implications on the timing of estrogen treatment in postmenopausal women.

Place, publisher, year, edition, pages
ENDOCRINE SOC , 2022. Vol. 107, no 5, p. E1879-E1889
Keywords [en]
estradiol, adipose tissue, menopause, insulin resistance, type 2 diabetes
National Category
Endocrinology and Diabetes Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:uu:diva-483563DOI: 10.1210/clinem/dgac042ISI: 000764767300001PubMedID: 35084504OAI: oai:DiVA.org:uu-483563DiVA, id: diva2:1693902
Funder
DiabetesfondenEU, Horizon 2020, H2020-MSCA-ITN-721236EXODIAB - Excellence of Diabetes Research in SwedenErnfors FoundationP.O. Zetterling FoundationSwedish Society for Medical Research (SSMF)Novo NordiskAvailable from: 2022-09-08 Created: 2022-09-08 Last updated: 2024-03-22Bibliographically approved
In thesis
1. Estrogen and its receptors in adipose tissue from women and men: Associations with age, adiposity and type 2 diabetes
Open this publication in new window or tab >>Estrogen and its receptors in adipose tissue from women and men: Associations with age, adiposity and type 2 diabetes
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity and its complications, such as insulin resistance and type 2 diabetes (T2D), are leading causes of morbidity and mortality globally. Adipose tissue is important for whole-body homeostasis, functioning as an energy storage reservoir and an endocrine organ. Estrogens mediate their effects through estrogen receptor alpha (ESR1) and beta (ESR2) and contribute to sex and menopause-related differences in body fat distribution. Moreover, estrogens can be produced from androgens in the adipose tissue by the enzyme aromatase. The overall aim of this thesis was to investigate the role of estrogen and estrogen signalling in human adipose tissue and their association with age, adiposity, and insulin resistance. 

In Paper I, we assessed ESR1 and ESR2 gene expression in subcutaneous adipose tissue (SAT) from pre- and postmenopausal women, and investigated the effects of estradiol on adipocyte glucose uptake. We found that ESR2 gene expression was higher in postmenopausal women than premenopausal women. Moreover, in late, but not pre- or early postmenopausal women, estradiol incubation reduced basal and insulin-stimulated glucose uptake, which corresponded to an increase in ESR2 gene expression levels. The inhibiting effect of estradiol on adipocyte glucose uptake was prevented using an ESR2 antagonist. 

Subsequently, in Paper II we assessed the role of ESR2 in SAT lipid and glucose metabolism and preadipocyte differentiation. ESR2 expression in SAT was inversely correlated with markers of central adiposity and positively correlated with markers of lipid accumulation. Moreover, ESR2 knockdown impaired subcutaneous preadipocyte differentiation and glucose utilization. 

In Paper III, we focused on adipocyte lipolysis in women, which is regulated, in part, by catecholamines. OCT3, which mediates catecholamine transport into adipocytes, where they can be degraded, was increased in SAT with age, and higher in postmenopausal women than premenopausal women. Moreover, its expression was negatively associated with markers of insulin resistance and ex vivo lipolysis. Estradiol incubation of SAT downregulated OCT3 gene expression, which may explain lower OCT3 gene expression in premenopausal compared to postmenopausal women. 

In Paper IV, we focused on the role of aromatase and estradiol in SAT from men. We found that aromatase expression was higher in SAT from men with obesity and T2D compared to subjects without obesity and T2D, respectively, and was positively associated with markers of central obesity and markers of insulin resistance. Contrastingly, ESR1 expression in SAT was lower in men with obesity and T2D compared to subjects without obesity and T2D, respectively, and negatively associated with markers of obesity and insulin resistance. ESR2 expression was higher in SAT from men with T2D compared to men without T2D. Estradiol reduced insulin-stimulated glucose uptake, however, neither testosterone, nor aromatase inhibition, altered adipocyte glucose uptake. 

In this thesis, we found that estrogen has important metabolic effects in adipose tissue, including regulating lipid accumulation, glucose uptake capacity, and catecholamine transport. Overall, our findings suggest that estrogen and estrogen receptors may have an important role in age-, menopausal- and sex-dependent differences in body fat distribution, and may serve as potential targets for the prevention and treatment obesity and insulin resistance. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 60
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2038
Keywords
Adipose tissue, estrogen, estrogen receptors, menopause, obesity, insulin resistance, type 2 diabetes.
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-524955 (URN)978-91-513-2076-2 (ISBN)
Public defence
2024-05-15, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2024-04-22 Created: 2024-03-22 Last updated: 2024-05-07Bibliographically approved

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Ahmed, FoziaKamble, Prasad G.Hetty, SusanneFanni, GiovanniVranic, MilicaSarsenbayeva, AsselKristofi, RobinAlmby, Kristina E.Svensson, Maria K.Pereira, Maria J.Eriksson, Jan

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Ahmed, FoziaKamble, Prasad G.Hetty, SusanneFanni, GiovanniVranic, MilicaSarsenbayeva, AsselKristofi, RobinAlmby, Kristina E.Svensson, Maria K.Pereira, Maria J.Eriksson, Jan
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