Impaired Preadipocyte Differentiation Into Adipocytes in Subcutaneous Abdominal Adipose of PCOS-Like Female Rhesus Monkeys

Abstract

Metabolic characteristics of polycystic ovary syndrome women and polycystic ovary syndrome-like, prenatally androgenized (PA) female monkeys worsen with age, with altered adipogenesis of sc abdominal adipose potentially contributing to age-related adverse effects on metabolism. This study examines whether adipocyte morphology and gene expression in sc abdominal adipose differ between late reproductive-aged PA female rhesus monkeys compared with age-matched controls (C). Subcutaneous abdominal adipose of both groups was obtained for histological imaging and mRNA determination of zinc finger protein 423 (Zfp423) as a marker of adipose stem cell commitment to preadipocytes, and CCAAT/enhancer binding protein (C/EBP)α/peroxisome proliferator-activated receptor (PPAR)δ as well as C/EBPα/PPARγ as respective markers of early- and late-stage differentiation of preadipocytes to adipocytes. In all females combined, serum testosterone (T) levels positively correlated with fasting serum levels of total free fatty acid (r(2) = 0.73, P < .002). PA females had a greater population of small adipocytes vs C (P < .001) in the presence of increased Zfp423 (P < .025 vs C females) and decreased C/EBPα (P < .003, vs C females) mRNA expression. Moreover, Zfp423 mRNA expression positively correlated with circulating total free fatty acid levels during iv glucose tolerance testing (P < .004, r(2) = 0.66), whereas C/EBPα mRNA expression negatively correlated with serum T levels (P < .02, r(2) = 0.43). Gene expression of PPARδ and PPARγ were comparable between groups (P = .723 and P = .18, respectively). Early-to-mid gestational T excess in female rhesus monkeys impairs adult preadipocyte differentiation to adipocytes in sc abdominal adipose and may constrain the ability of this adipose depot to safely store fat with age.

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

“…Serum adiponectin levels were reduced in our PCOS mouse model, and this effect was protected by global loss of AR function but not by neuronor granulosa cell-specific loss of AR actions. Altered adipose structure has been reported in PCOS women (43) and is linked with androgen excess, as prenatally androgenized female monkeys display impaired adipogenesis (44). Adipocyte hypertrophy and hepatic steatosis (resembling nonalcoholic fatty liver disease) were exhibited in all DHT-treated wild-type groups but absent in global ARKO females.…”

The role of sex steroids in white adipose tissue adipocyte function

“…Androgen administration to women results in the reduction of late-stage differentiation of pre-adipocytes to adipocytes (Chazenbalk et al 2013). These findings suggest that excess androgens (i.e., PCOS) would decrease the lipid storage capacity in subcutaneous abdominal WAT and promote lipotoxicity (Chazenbalk et al 2013, Keller et al 2014. This finding occurs apart from changes in insulin sensitivity, which affect lipogenesis, particularly in PCOS patients.…”

Androgens in polycystic ovary syndrome

“…Neonatal androgenization of mice decreases adiponectin levels [42], whereas prenatally T-treated sheep exhibit elevated leptin concentrations [43]. In the female rhesus monkey PCOS model, prenatal T excess leads to impaired adult preadipocyte differentiation to adipocytes in abdominal adipose, which may constrain the ability of the adipose depot to safely store fat, thus promoting lipotoxicity [44]. Prenatal T-treated sheep also exhibit changes in adipocyte morphology, however, these are not prevented by cotreatment with an androgen antagonist, inferring that estrogenic effects via the aromatization of T to estradiol may be predominant in the altered programming [43].…”