Dehydroepiandrosterone reduces preadipocyte proliferation via androgen receptor

Abstract

Several studies have suggested that both testosterone and dehydroepiandrosterone (DHEA) have weight-reducing and antidiabetic effects, especially in rodent studies; however, the precise mechanism of their action remains unclear. Here, we investigated the effect of DHEA on cell growth in adipose tissue. The appearance of senescence-associated β-galactosidase in stromal vascular fraction (SVF) isolated from Otsuka Long-Evans Tokushima fatty rats, an animal model of inherent obese type 2 diabetes, was prevented by DHEA administration. Next, the effects of DHEA and testosterone were compared in vivo and in vitro to evaluate whether these hormones influence cell growth in adipose tissue. Both DHEA and testosterone reduced body weight and epididymal fat weight equivalently when administered for 4 wk. To assess the effect of DHEA and testosterone on cell growth in adipose tissue, 5-bromo-2'-deoxyuridine (BrdU) uptake by SVF was measured. Quantification analysis of BrdU uptake by examining DNA isolated from each SVF revealed that treatment with DHEA and testosterone reduced cell replication. These results indicated that DHEA- and testosterone-induced decreased adiposity was associated with reduced SVF growth. Incubation with DHEA and testosterone equally decreased BrdU uptake by 3T3-L1 preadipocytes. Pretreatment with the androgen receptor (AR) inhibitor flutamide, but not the estrogen receptor inhibitor fulvestrant, abolished these effects. Knockdown of AR with siRNA also inhibited DHEA-induced decreases in BrdU uptake. These results suggest that DHEA-induced growth suppression of preadipocytes is mediated via AR. Therefore, both DHEA and testosterone similarly decrease adipocyte growth possibly via a common mechanism.

Steroid biosynthesis in adipose tissue

“…indicating the presence of 3βHSD enzyme activity in metabolizing DHEA and its subsequent influence in adipocyte development (69). 3βHSD activity in converting DHEA into androstenedione was also demonstrated in breast adipose stromal cells from premenopausal women (70).…”

Adipocytes in Skin Health and Disease

“…Mice that express enhanced levels of the androgen receptor (AR) show decreased fat mass and adipocyte size (Blouin et al 2009;Semirale et al 2011) by preventing the commitment of preadipocytes (Chazenbalk et al 2013), promoting lipolysis (Blouin et al 2009) and blocking preadipocyte proliferation (Fujioka et al 2012). Androgens induce epidermal hyperplasia and affect the skin's barrier function (Kao et al 2001).…”

Effects of DHEA on metabolic and endocrine functions of adipose tissue

“…Exogenously administered DHEA inhibited fat accumulation or reduced visceral fat pads in young and adult rodents [14][15][16][17]30]. DHEA has also been shown to protect against visceral obesity in rats fed a high-fat diet [29,31].…”

“…In experimental animals, DHEA attenuates body weight gain without affecting food intake [15,16,29]. Exogenously administered DHEA inhibited fat accumulation or reduced visceral fat pads in young and adult rodents [14][15][16][17]30].…”

“…Because DHEA has been found to increase PPARγ mRNA levels in rat adipose tissue [14,15], it seems likely that the upregulation of PPARγ expression by DHEA is mediated through the activation of AR. Furthermore, AR has been proposed to be required for the effect of DHEA on preadipocyte proliferation [16]. Studies in rodents have shown that DHEA treatment also leads to a substantial increase in PPARα mRNA levels in adipose tissue [17,18].…”