1. Estradiol-driven metabolism in transwomen associates with reduced circulating extracellular vesicle microRNA-224/452
- Author
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Hetty C M Sips, Huayu Zhang, Patrick C.N. Rensen, Rienk Nieuwland, Ton J. Rabelink, Wendy Stam, Anton Jan van Zonneveld, Sander Kooijman, Maartje Klaver, Ronald W. A. L. Limpens, Barend W. Florijn, Martin den Heijer, Jurriën Prins, Maaike Hanegraaf, Roel Bijkerk, Jacques M.G.J. Duijs, Bas B. van Rijn, Eline N. Kuipers, VU University medical center, Internal medicine, APH - Aging & Later Life, Amsterdam Gastroenterology Endocrinology Metabolism, Clinical Genetics, Obstetrics & Gynecology, Laboratory for Experimental Clinical Chemistry, and ACS - Microcirculation
- Subjects
Adult ,Male ,medicine.medical_specialty ,Hormone Replacement Therapy ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,Down-Regulation ,Adipose tissue ,White adipose tissue ,Transgender Persons ,Energy homeostasis ,Cohort Studies ,Extracellular Vesicles ,Mice ,Young Adult ,Endocrinology ,SDG 3 - Good Health and Well-being ,Cell-Derived Microparticles ,Internal medicine ,microRNA ,Adipocytes ,medicine ,Animals ,Homeostasis ,Humans ,Gene silencing ,Adipogenesis ,Estradiol ,Chemistry ,General Medicine ,Extracellular vesicle ,Middle Aged ,Mice, Inbred C57BL ,MicroRNAs ,Gene Expression Regulation ,Lipogenesis ,Clinical Study ,Female ,RNA Interference ,Energy Metabolism ,Transsexualism - 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.
- Published
- 2021