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ObjectiveTo examine whether subcutaneous (SC) abdominal adipose stem cell differentiation into adipocytes in vitro predicts insulin sensitivity (Si) in vivo in normal-weight women with polycystic ovary syndrome (PCOS) and controls.DesignProspective cohort study.SettingAcademic medical center.Patient(s)Eight normal-weight women with PCOS and 8 age- and body mass index-matched controls.Intervention(s)Women underwent circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total-body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy.Main outcome measure(s)PPARγ and CEBPa gene expression and lipid content of adipocytes matured in vitro were compared between women with PCOS and control women, and correlated with patient characteristics, systemic Si, and adipose insulin resistance (adipose-IR).Result(s)Serum androgen levels, adipose-IR, and percentage of android fat were greater in women with PCOS than control women. Stem cell PPARγ and CEBPa gene expression increased maximally by day 12 without a female-type effect. In control cells, gene expression positively correlated with fasting serum insulin levels (both genes) and adipose-IR (CEBPa) and negatively correlated with Si (CEBPa). Conversely, CEBPa gene expression in PCOS cells negatively correlated with adipose-IR and serum free testosterone, whereas total lipid accumulation in these cells positively corelated with Si.ConclusionIn normal-weight women with PCOS, accelerated SC abdominal adipose stem cell differentiation into adipocytes in vitro favors Si in vivo, suggesting a role for hyperandrogenism in the evolution of metabolic thrift to enhance fat storage through increased cellular glucose uptake.

BackgroundNormal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis.ResultsSC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two-sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12.ConclusionsIn normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.

ObjectiveTo examine whether abnormal subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes in polycystic ovary syndrome (PCOS) correlates with hyperandrogenism.DesignProspective cohort study.SettingAcademic medical center.Patient(s)Eight normal-weight women with PCOS and eight normoandrogenic ovulatory (control) women matched for age and body mass index.Intervention(s)Circulating hormone and metabolic measurements, intravenous glucose tolerance testing, total body dual-energy X-ray absorptiometry, and SC abdominal fat biopsy.Main outcome measure(s)In vitro ASC commitment to preadipocytes (ZFP423 protein expression, day 0.5), preadipocyte differentiation to adipocytes (PPARγ gene expression, day 3) and adipocyte lipid content (Oil-Red-O fluorescence, day 12) comparisons correlated with clinical outcomes.Result(s)In women with PCOS, SC abdominal ASCs compared with those of control women showed exaggerated commitment to preadipocytes and had greater lipid content in newly formed adipocytes after in vitro maturation. In all women combined, ZFP423 protein expression negatively correlated with fasting plasma glucose levels whereas the lipid content of newly formed adipocytes positively correlated with both PPARγ gene expression and serum free testosterone levels.Conclusion(s)In normal-weight women with PCOS compared with the control group, exaggerated SC abdominal ASC commitment to preadipocytes and enhanced adipocyte lipid content during maturation in vitro negatively and positively correlate with circulating fasting glucose and androgen levels, respectively, as a possible mechanism to maintain glucose-insulin homeostasis when fat accretion is accelerated.

Objective: The Craniofacial Condition Quality of Life Scale (CFC-QoL) was used to evaluate the relationship between surgical burden and quality of life (QoL)., Design: Patient-parent dyads completed the CFC-QoL which queries the following QoL domains: Bullying, Peer Problems, Psychological Impact, Family Support, Appearance Satisfaction, and Desire for Appearance Change. Stepwise multivariate linear regressions were performed for each QoL domain., Setting: Urban tertiary care center., Patients, Participants: Pediatric patients with facial differences, and their parents., Intervention: Survey study., Main Outcome Measure(s): Demographic, diagnostic, and surgical characteristics were collected. Surgical burden was calculated as the standard deviation from the mean number of surgeries per diagnostic cohort., Result: Patients ( N   =  168) were majority female (57.1%) and Hispanic (64.3%). Diagnoses were cleft lip and/or palate (CLP, n   =  99) or other craniofacial conditions (CFC, n   =  69). Average patient age was 2.3  ±  5.6 years at first reconstructive surgery and 12.3  ±  3.4 years at study enrollment. Patients received an average of 4.3  ±  4.1 reconstructive surgeries.Worse Bullying was associated with higher surgical burden. Worse Peer Problems was associated with higher surgical burden, but only for children with non-CLP CFCs. Worse Family Support was associated with CFC diagnosis, female sex, and higher surgical burden. Worse Psychological Impact was associated with higher surgical burden. Worse Appearance Satisfaction was associated with younger age and with lower surgical burden. Greater Desire for Appearance Change was associated with older age, higher surgical burden, CLP diagnosis, female sex, and non-Hispanic ethnicity. Socioeconomic status did not predict QoL per patient self- or parent-proxy report., Conclusions: Higher surgical burden was associated with worse QoL outcomes in multiple domains.