Estradiol-driven metabolism in transwomen associates with reduced circulating extracellular vesicle microRNA-224/452

Barend W. Florijn*, Jacques M.G.J. Duijs, Maartje Klaver, Eline N. Kuipers, Sander Kooijman, Jurrien Prins, Huayu Zhang, Hetty C.M. Sips, Wendy Stam, Maaike Hanegraaf, Ronald W.A.L. Limpens, Rienk Nieuwland, Bas B. van Rijn, Ton J. Rabelink, Patrick C.N. Rensen, Martin den Heijer, Roel Bijkerk, Anton Jan van Zonneveld

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 under lying 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 bro wn 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 n etwork that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.

Original languageEnglish
Pages (from-to)539-552
Number of pages14
JournalEuropean Journal of Endocrinology
Volume185
Issue number4
DOIs
Publication statusPublished - 27 Aug 2021

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