Adolescent polycystic ovary syndrome (PCOS) is characterized by androgen excess and oligomenorrhea, and commonly driven by hepato-visceral fat excess (“central obesity”) ensuing from a mismatch between prenatal and postnatal nutrition, on a background of genetic susceptibility. There is no approved treatment for adolescent PCOS. We report the pooled results of 2 pilot studies in nonobese girls with PCOS (N = 62, age 15.8 years) that compared the effects of randomized treatment for 1 year, either with an oral estro-progestogen contraceptive (OC), or with a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET, targeting the excess of ectopic fat). Auxological and endocrine-metabolic variables (including fasting insulin, androgens, high-molecular-weight adiponectin [HMW-adiponectin], and microRNA [miR]-451a), body composition (dual x-ray absorptiometry) and hepato-visceral fat (magnetic resonance imaging) were assessed on- and posttreatment. Data from menstrual diaries were combined with weekly salivary progesterone measurements to infer ovulation rates during the second and fourth quarter of the posttreatment year. OC and SPIOMET treatment reduced the androgen excess comparably, and had no differential effects on total-body lean or fat mass. However, SPIOMET was accompanied by more broadly normalizing effects, including on hepato-visceral fat and on circulating insulin, HMW-adiponectin, and miR-451a. On average, there were 3-fold more ovulations post-SPIOMET than post-OC; normovulation was only observed after SPIOMET; anovulation was >10-fold more prevalent post-OC. Pooled results of randomized studies in nonobese adolescent girls with PCOS indicate that SPIOMET treatment leads to an overall healthier, more insulin-sensitive condition—with less ectopic fat—than OC treatment, and to a more normal posttreatment ovulation rate.

Context Brown adipose tissue (BAT) is particularly abundant in neonates but its association with measures of adiposity and metabolic health in early infancy is poorly delineated. Besides sustaining non-shivering thermogenesis, BAT secretes brown adipokines that act on systemic metabolism. The chemokine CXCL14 has been identified as a brown adipokine in experimental studies. Objective To determine the relationships among BAT activity, adiposity and circulating CXCL14 levels in the first year of life in girls and boys. Design, setting and participants Indices of fat accretion, circulating endocrine-metabolic parameters and serum CXCL14 levels were assessed longitudinally in a cohort of infants at birth and at 4 and 12 months. BAT activity was estimated using infrared thermography only at age 12 months. Main outcome measures Weight and length Z-scores, total and abdominal fat content (by DXA), BAT activity at the posterior-cervical and supraclavicular regions, serum levels of glucose, insulin, insulin-like growth factor-I, high-molecular-weight adiponectin and CXCL14; CXCL14 transcript levels in neonatal BAT and liver. Results Posterior-cervical BAT was more active in girls than in boys (P=0.02). BAT activity was negatively associated with adiposity parameters only in girls. CXCL14 levels were higher in girls than in boys at age 12 months and correlated positively with the area of active posterior-cervical BAT in girls. Neonatal BAT showed high CXCL14 gene expression levels. Conclusions BAT activity and the levels of CXCL14 -a potential surrogate of BAT activity, are sex-specific in the first year of life. Posterior-cervical BAT activity associates negatively with indices of adiposity only in girls.

ObjectiveCXCL14 (C-X-C motif chemokine ligand-14) is a chemokine released by active brown fat, showing protective effects against insulin resistance in experimental models. Polycystic ovary syndrome (PCOS) in adolescent girls is usually related to hepato-visceral fat excess and insulin resistance, and associates with comorbidities such as type 2 diabetes. Treatment with a low-dose combination of one antiandrogen and antimineralocorticoid drug (spironolactone) and two insulin sensitizers (pioglitazone/metformin) (SPIOMET) is particularly effective in improving these metabolic derangements. Adipose tissue may be involved in the metabolic alterations of PCOS, and it is a likely target of therapeutic action. We investigated the alterations in CXCL14 levels and the effects of drugs composing SPIOMET treatment on CXCL14 in human adipocytes.Research design and methodsWe studied 51 adolescent patients with PCOS and 21 age-matched healthy controls. Thirty-one adolescent patients with PCOS under SPIOMET or oral contraception-based treatment were also studied. For studies in vitro, Simpson Golabi Behmel Syndrome (SGBS) adipose cells were used. Gene expression for CXCL14 and other genes was quantified using quantitative real-time PCR. The levels of CXCL14 and adipokines in serum and cell culture media were determined by ELISA.ResultsSerum CXCL14 levels are reduced in patients with PCOS. One-year SPIOMET treatment normalized CXCL14 concentrations and improved the metabolic status of patients with PCOS. Pioglitazone induced CXCL14 expression in differentiating human SGBS adipocytes, in parallel with the induction of marker genes of brown adipogenesis. Spironolactone induced CXCL14 expression and release in differentiated human adipocytes.ConclusionInsulin sensitization with SPIOMET normalizes the abnormally low levels of CXCL14 in girls with PCOS. This is consistent with the effects of pioglitazone and spironolactone inducing CXCL14 expression and promoting a brown-like phenotype in adipocytes. CXCL14 may be a novel biomarker for PCOS as well as a potential mediator of the beneficial effects of the SPIOMET combination and may hold promise as a therapeutic modulator of the disorder.Trial registration numbersISRCTN29234515 and ISCRCTN11062950.

ObjectiveBone morphogenetic protein-8B (BMP8B) is an adipokine produced by brown adipose tissue (BAT) contributing to thermoregulation and metabolic homeostasis in rodent models. In humans, BAT activity is particularly relevant in newborns and young infants. We assessed BMP8B levels and their relationship with BAT activity and endocrine-metabolic parameters in young infants to ascertain its potentiality as biomarker in early life.Materials and MethodsBMP8B concentrations were assessed longitudinally by ELISA in a cohort of 27 girls and 23 boys at birth, and at age 4 and 12 months, together with adiposity parameters (DXA), and circulating endocrine-metabolic variables. BAT activity was measured by infrared thermography. BMP8B gene expression (qRT-PCR) was determined in BAT, white fat, and liver samples from neonatal necropsies, and in placenta and cord blood.ResultsBMP8B levels were high at birth, particularly in boys (P = 0.04 vs. girls), declined progressively, and remained well above those in healthy adults and pregnant women at age 1 year (P < 0.05 and P < 0.001, respectively). Neonatal BMP8B transcript levels were higher in BAT than in white fat, liver and cord blood. Circulating BMP8B levels during the first year of life marginally correlated with bone mineral density and gains in lean mass.ConclusionBMP8B levels are high at birth and decline progressively over the first year of life remaining above adult levels. Although changes in BMP8B concentrations overall reflect those in BAT activity during development, BMP8B levels are unlikely to be useful to predict individual variations in endocrine-metabolic status and BAT activity in healthy young infants.

Summary Background Girls with obesity and polycystic ovary syndrome (PCOS) and women with PCOS have altered gut microbiota. Objective To study the gut microbiota composition of girls with PCOS without obesity (age, 15.8 years; body mass index [BMI] 25 kg/m2) and the effects of randomized treatments with an oral contraceptive (OC, N = 15) or with spironolactone‐pioglitazone‐metformin (SPIOMET, N = 15) for 1 year. Thirty‐one age‐matched girls served as controls. Methods 16S ribosomal subunit gene amplicon sequencing was performed in stool samples from all subjects; samples from 23 out of 30 girls with PCOS (OC, N = 12; SPIOMET, N = 11) were available for analysis post‐treatment. Clinical and endocrine‐metabolic variables were measured before and after intervention. Results Girls with PCOS had decreased diversity alpha, altered microbiota pattern and taxonomic profile with more abundance of Family XI (P = .002), and less abundance of family Prevotellaceae (P = .0006) the genus Prevotella (P = .0001) and Senegalimassilia (P < .0001), as compared to controls. Family XI abundance related positively to hepato‐visceral fat (R = 0.453; P = .0003). SPIOMET treatment, but not OC, normalized the abundance of Family XI. Prevotellaceae, Prevotella and Senegalimassilia abundance remained unchanged after either treatment. Conclusion SPIOMET's spectrum of normalizing effects in girls with PCOS is herewith broadened as to include Family XI abundance in gut microbiota.

Summary Background The sequence of prenatal growth restraint and postnatal catch‐up growth leads to a thicker intima‐media and more pre‐peritoneal fat by age 3–6 years. Objectives To study whether carotid intima‐media thickness (cIMT) and pre‐peritoneal fat differ already between catch‐up small‐for‐gestational‐age (SGA) infants and appropriate‐for‐gestational‐age (AGA) controls in late infancy (ages 1 and 2 years) and whether such differences – if any – are accompanied by differences in cardiac morphology and function. Methods Longitudinal assessments included body height and weight; fasting glucose, insulin, Insulin‐like growth factor (IGF‐I), high‐molecular‐weight adiponectin; body composition (by absorptiometry); cIMT, aortic IMT, pre‐peritoneal fat partitioning (by ultrasound); cardiac morphometry and function (by echocardiography) in AGA and SGA infants at birth, at age 1 year (N = 87), and again at age 2 years (N = 68). Results Catch‐up SGA infants had already a thicker cIMT than AGA controls at ages 1 and 2 years, and more pre‐peritoneal fat by age 2 years (all p values between <0.01 and <0.0001); all cardiac and endocrine‐metabolic results were similar in AGA and SGA infants at ages 1 and 2 years. Conclusions From late infancy onwards, catch‐up SGA infants have a thicker cIMT and more pre‐peritoneal fat than AGA controls, but their cardiac morphology and function remain reassuringly similar.

Summary Background Insulin resistance and hepato‐visceral (central) fat excess are thought to contribute to an earlier timing of adrenarche/pubarche and puberty/menarche; this earlier timing in turn relates often to a mismatch between prenatal and postnatal weight gain, which can be estimated by calculating the Z‐score change from birth weight (BW) to body mass index (BMI) in childhood. Methods We tested the hypothesis that this calculation may serve as a proxy of insulin resistance and hepato‐visceral adiposity in prepuberty by reappraising a cohort of children (mean age, 8.5 years), born appropriate‐ (AGA, n = 41) or small‐for‐gestational age (SGA, n = 45), followed since birth (n = 76) or since the age of 3 years (n = 10). Assessments included anthropometry; fasting glucose and insulin; liver volume; and hepatic fat, subcutaneous fat, and visceral fat in the abdominal region (by magnetic resonance imaging [MRI]). Results Z‐score change BW‐BMI closely associated to central fat (R = 0.74; P < .0001) and insulin resistance (R = 0.71; P < .0001). Conclusion These results suggest that Z‐score change BW‐BMI could be viewed as a simple candidate‐marker for hepato‐visceral adiposity and insulin resistance in prepubertal children.

Summary S100A4 is a marker of subcutaneous adipose tissue dysfunction. Polycystic ovary syndrome (PCOS) is often driven by hepato‐visceral adiposity. PCOS phenotypes are normalized more by reduction of central fat with spironolactone/pioglitazone/metformin (SPIOMET) than by oral contraceptive (OC) treatment. We studied whether circulating S100A4 concentrations are high in adolescents with PCOS and, if so, whether they normalize more with OC or SPIOMET. Assessments included circulating S100A4, endocrine markers, body composition, abdominal fat partitioning in controls (n = 12) and girls with PCOS (n = 51; age 15.8 y; body mass index [BMI] 24.5 kg/m2), and 1‐year changes in girls with PCOS randomized for OC (n = 27) or SPIOMET (n = 24) treatment. Mean S100A4 concentrations were 71% higher (P < 0.001) in girls with PCOS than in controls and associated with hepato‐visceral adiposity (r = 0.47; P = 0.001); S100A4 concentrations decreased more (P < 0.01) with SPIOMET, those decreases associating to hepato‐visceral fat loss (r = 0.50; P < 0.0001). S100A4 may become a circulating marker of hepato‐visceral fat excess in adolescents with PCOS.