TY - JOUR
T1 - Estradiol-driven metabolism in transwomen associates with reduced circulating extracellular vesicle microRNA-224/452
AU - Florijn, Barend W.
AU - Duijs, Jacques M. G. J.
AU - Klaver, Maartje
AU - Kuipers, Eline N.
AU - Kooijman, Sander
AU - Prins, Jurrien
AU - Zhang, Huayu
AU - Sips, Hetty C. M.
AU - Stam, Wendy
AU - Hanegraaf, Maaike
AU - Limpens, Ronald W. A. L.
AU - Nieuwland, Rienk
AU - van Rijn, Bas B.
AU - Rabelink, Ton J.
AU - Rensen, Patrick C. N.
AU - den Heijer, Martin
AU - Bijkerk, Roel
AU - van Zonneveld, Anton Jan
N1 - Funding Information: This study was supported by funding provided by the Netherlands Heart Foundation in the context of consortia: Queen of Hearts (A J V Z, B W F, Publisher Copyright: © 2021 The authors.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114608241&partnerID=8YFLogxK
U2 - https://doi.org/10.1530/EJE-21-0267
DO - https://doi.org/10.1530/EJE-21-0267
M3 - Article
C2 - 34342596
SN - 0804-4643
VL - 185
SP - 539
EP - 552
JO - European journal of endocrinology
JF - European journal of endocrinology
IS - 4
ER -