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.
Highlights
Considered little more than a passive reservoir for energy storage, adipose tissue is recognized as an active endocrine organ, involved in the regulation of metabolism and whole-body energy homeostasis
Androgen Receptor Protein Is Expressed in IMBAT Preadipocytes and Adipocytes
Androgen receptor protein was detected by immunohistochemistry in preadipocytes and differentiated IMBATs
Summary
Considered little more than a passive reservoir for energy storage, adipose tissue is recognized as an active endocrine organ, involved in the regulation of metabolism and whole-body energy homeostasis. Adipose tissue exists in two main forms: white adipose tissue (WAT) and brown adipose tissue (BAT), and these differ in both morphology and physiology. WAT stores large amounts of energy in a unilocular lipid droplet, ready to be released as fatty acids for any future metabolic needs [5] whereas BAT is distinguished by its unique capacity to dissipate energy as heat in a process called non-shivering thermogenesis [6]. BAT is characterized by multiple small lipid droplets and abundant mitochondria and responds to cold or adrenergic stimuli by uncoupling oxidative phosphorylation from ATP synthesis to generate heat via the actions of uncoupling protein 1 (UCP1) [6]. It has become increasingly recognized that there is an inverse correlation between the amount of functional BAT and BMI, suggesting that its energy dissipating function may play a role in the development of obesity [8]
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