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

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

doi:10.1530/eje-21-0267

Abstract

ObjectiveSex 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.MethodsFollowing 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.ResultsEstradiol 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).ConclusionThis study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.

Highlights

Sex hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism [1]
By further applying in silico analysis of the RNA sequencing (RNA-seq) data with the Ingenuity Pathway Analysis (IPA) tool, we identified mitochondrial dysfunction and insulin receptor signaling in BAT as significant top canonical pathways affected (Supplementary Fig. 5)
This study demonstrates that estradiol in transwomen lowers circulating miR-224 and -452 carried in extracellular vesicles

Summary

Introduction

Sex hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism [1]. Regular estradiol administration (in combination with antiandrogenic compounds) in transwomen may affect energy metabolism by increasing total body fat [3], fasting insulin, and HOMA of insulin resistance (HOMA-IR) [4], thereby reducing peripheral insulin sensitivity [5]. This sex hormone-associated decline in metabolic health increases the risk for type 2 diabetes and future cardiovascular disease (CVD) in transwomen [6]. Given that increasing evidence is linking estrogen regulation in adipose tissue to whole-body metabolism [10], sex-specific, adipose tissue-derived miRs [11] could potentially alter metabolism at distal tissue sites [12]

Methods

Results

Conclusion