Androgen Reduces Mitochondrial Respiration in Mouse Brown Adipocytes: A Model for Disordered Energy Balance in Polycystic Ovary Syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is associated with an adverse metabolic profile including reduced postprandial thermogenesis. Although abnormalities in adipose tissue function have been widely reported in women with PCOS, less is known about direct effects of androgen on white and, particularly, brown adipocytes. The purpose of this study was to investigate the effect of the nonaromatizable androgen dihydrotestosterone (DHT) on (1) lipid accumulation and expression of adipogenic markers in immortalized mouse brown adipose cell lines (IMBATs), (2) mitochondrial respiration in IMBATs, (3) mitochondrial DNA content and gene expression, (4) expression of brown adipose tissue (BAT) markers and thermogenic activation. In addition, we profiled the relative levels of 38 adipokines secreted from BAT explants and looked at androgen effects on adipokine gene expression in both IMBATs and immortalized mouse white adipose (IMWATs) cell lines. Androgen treatment inhibited IMBAT differentiation in a dose-dependent manner, reduced markers of adipogenesis, and attenuated the β-adrenoceptor-stimulated increase in uncoupling protein-1 (UCP1) expression. In explants of mouse interscapular BAT, androgen reduced expression of UCP1, peroxisome proliferator-activated receptor-γ coactivator-1 (PCG-1) and Cidea. Significantly, as well as affecting genes involved in thermogenesis in BAT, androgen treatment reduced mitochondrial respiration in IMBATs, as measured by the Seahorse XF method. The results of this study suggest a role for excess androgen in inhibiting brown adipogenesis, attenuating the activation of thermogenesis and reducing mitochondrial respiration in BAT. Together, these data provide a plausible molecular mechanism that may contribute to reduced postprandial thermogenesis and the tendency to obesity in women with PCOS.

Sex Differences in Brown Adipose Tissue Function: Sex Hormones, Glucocorticoids, and Their Crosstalk

“…In primary brown adipocytes of rodents, testosterone inhibited mitochondrial biogenesis, brown adipocyte differentiation, and norepinephrine-induced lipolysis (115,116,124). In immortalized mouse brown adipose cells, DHT (a nonaromatizable androgen) dose-dependently inhibited differentiation, isoproterenol-stimulated Ucp1 mRNA expression, and mitochondrial respiration, and these findings were confirmed in explants of mouse BAT (133). However, direct in vivo effects of androgens appear controversial.…”

Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females

“…In cellular models, differentiation of brown adipocytes is inhibited by androgen in a dosedependent manner, leading to decreased expression of UCP1. These changes correspond to a reduction in the mitochondrial number and "whitening" of the interscapular BAT in androgeninduced PCOS models (140). This mitochondrial dysfunction is supported by a decrease in other mitochondrial proteins including PGC-1a and Cidea (cell death-inducing DNA fragmentation factor-like effector A).…”

Three-Dimentional Visualization of Electroacupuncture Activates Brown Adipose Tissue via Sympathetic Innervation in PCOS Rats

“…Recent studies have shown that women with PCOS have lower BAT activity compared to controls, and BAT thermogenesis and the β-adrenoceptor-stimulated increase in UCP1 expression are negatively associated with androgen levels in PCOS [24,25] . Similarly, transplantation of BAT into PCOS-like rats reverses anovulation, hyperandrogenism, and polycystic ovaries and significantly stabilizes menstruation and normalizes systemic insulin sensitivity [8] .…”