Estradiol-driven metabolism in transwomen associates with reduced circulating extracellular vesicle microRNA-224/452. Issue 4 (27th August 2021)

• Record Type: Journal Article
• Authors: Florijn, Barend W; Duijs, Jacques M G J; Klaver, Maartje; Kuipers, Eline N; Kooijman, Sander; Prins, Jurrien; Zhang, Huayu; Sips, Hetty C M; Stam, Wendy; Hanegraaf, Maaike; Limpens, Ronald W A L; Nieuwland, Rienk; van Rijn, Bas B; Rabelink, Ton J; Rensen, Patrick C N; den Heijer, Martin; Bijkerk, Roel; van Zonneveld, Anton Jan
• Is Part Of: European journal of endocrinology. Volume 185:Issue 4(2021)
• Page Start: 539
• Page End: 552
• Publication Date: 2021-08-27
• Subjects: Endocrinology -- Periodicals; 616.4005
• DOI: 10.1530/EJE-21-0267
• Languages: English
• ISSNs: 0804-4643

Abstract

Abstract: Objective: Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the underlying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice. Methods: Following plasma miR-sequencing (seq) in a transwomen discovery ( n = 20) and validation cohort ( n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice ( n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes. Results: Estradiol in transwomen lowered plasma miR-224 and -452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and brown adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose). Conclusion: This study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.