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During pregnancy, maternal polyunsaturated fatty acids (PUFA) are transferred to the fetus through the placenta by specific FA transporters (FATP). A higher perinatal exposure to n-6 over n-3 PUFA could be linked to excess fat mass and obesity development later in life. In this context, we aimed to assess the associations between long chain PUFAs (LC-PUFAs) (n-6, n-3, and n-6/n-3 ratios) measured in the placenta at term birth with obesity-related parameters in the offspring at 6 years of age and assess whether these associations are dependent on the placental relative expression of fatty acid transporters. As results, the PUFAn-6/PUFAn-3 ratio was 4/1, which scaled up to 15/1 when considering only the arachidonic acid/eicosapentaenoic acid ratio (AA/EPA ratio). Positive associations between the AA/EPA ratio and offspring’s obesity risk parameters were found with weight-SDS, BMI-SDS, percent fat mass-SDS, visceral fat, and HOMA-IR (r from 0.204 to 0.375; all p < 0.05). These associations were more noticeable in those subjects with higher expression of fatty acid transporters. Therefore, in conclusion, a higher placental AA/EPA ratio is positively associated with offspring’s visceral adiposity and obesity risk parameters, which become more apparent in subjects with higher expressions of placental FATPs. Our results support the potential role of n-6 and n-3 LC-PUFA in the fetal programming of obesity risk in childhood. For the present study, 113 healthy pregnant women were recruited during the first trimester of pregnancy and their offspring were followed up at 6 years of age. The fatty acid profiles and the expression of fatty acid transporters (FATP1 and FATP4) were analyzed from placental samples at birth. Associations between LC-PUFA (n-6, n-3, and n-6/n-3 ratios) and obesity risk parameters (weight, body mass index (BMI), percent fat mass, visceral fat, and homeostatic model assessment of insulin resistance (HOMA-IR)) in the offspring at 6 years of age were examined.

BACKGROUND: Cytochrome P450 4F3 (CYP4F3) is an ω-hydroxylase that oxidizes leukotriene B4 (LTB4), prostaglandins, and fatty acid epoxides. LTB4 is synthesized by leukocytes and acts as a chemoattractant for neutrophils, making it an essential component of the innate immune system. Recently, involvement of the LTB4 pathway was reported in various immunological disorders such as asthma, arthritis, and inflammatory bowel disease. We report a 26-year-old female with a complex immune phenotype, mainly marked by exhaustion, muscle weakness, and inflammation-related conditions. The molecular cause is unknown, and symptoms have been aggravating over the years. METHODS: Whole exome sequencing was performed and validated; flow cytometry and enzyme-linked immunosorbent assay were used to describe patient's phenotype. Function and impact of the mutation were investigated using molecular analysis: co-immunoprecipitation, western blot, and enzyme-linked immunosorbent assay. Capillary electrophoresis with ultraviolet detection was used to detect LTB4 and its metabolite and in silico modelling provided structural information. RESULTS: We present the first report of a patient with a heterozygous de novo missense mutation c.C1123 > G;p.L375V in CYP4F3 that severely impairs its activity by 50% (P 0.9 for both co-immunoprecipitation with POR and Cytb5). In silico modelling of CYP4F3 in complex with POR and Cytb5 suggests that the loss of catalytic activity of the mutant CYP4F3 is explained by a disruption of an α-helix that is crucial for the electron shuffling between the electron carriers and CYP4F3. Interestingly, zileuton still inhibits ex vivo LTB4 production in patient's whole blood to 2% of control (P

Introduction: Suprasellar tuberculoma are extremely rare in children and most of those patients present with headache, vomiting, visual disturbances, and hypofunction of the pituitary gland. In this case report, we present a girl with tuberculosis, who developed significant weight gain in combination with pituitary dysfunction, which recovered after antituberculosis treatment. Case presentation: An 11-year old girl presented with headache, fever and anorexia that progressively evolved into an encephalopathic status with cranial nerves III and VI paresis. Brain MRI showed meningeal contrast capture along cranial nerves II (including optic chiasm), III, V and VI bilaterally and multiple contrast enhancing brain parenchyma lesions. Tuberculin skin test was negative but interferon-gamma release assay was positive. The clinical and radiological working diagnosis was consistent with tuberculous meningoencephalitis. Pulse corticosteroids for three days and quadruple antituberculosis therapy were started and the girl demonstrated obvious improvement of her neurological symptoms. However, after a few months of therapy she developed remarkable weight gain (+20 kg in one year) and growth arrest. Her hormone profile revealed insulin resistance (homeostasis model assessment-estimated insulin resistance (HOMA-IR) 6.8) despite putative growth hormone deficiency (circulating insulin-like growth factor-I (IGF-I) 104 μg/L (-2.4 SD)). Follow-up brain MRI showed a decrease in basal meningitis, but increased parenchymal lesions in the suprasellar region extending medially into the nucleus lentiformis, with now a voluminous tuberculoma at this site. Antituberculosis treatment was continued for a total of 18 months. The patient improved clinically, she regained her pre-illness Body Mass Index (BMI) SDS and her growth rate increased slightly. On the hormonal side, disappearance of insulin resistance (HOMA-IR 2.5) and an increase in IGF-I (175 μg/L, -1.4 SD) was noted, and her last brain MRI showed a remarkable volume reduction of the suprasellar tuberculoma. Discussion/Conclusion: Suprasellar tuberculoma can have a very dynamic presentation during the active stage of the disease, which can be reversed by prolonged antituberculosis treatment. Previous studies showed that the tuberculous process can also cause long term and irreversible changes in the hypothalamic-pituitary axis. Prospective studies are however needed in the pediatric population to know the exact incidence and type of pituitary dysfunction.

Introduction Polycystic ovary syndrome (PCOS) in women associates with raised levels of circulating thyroid stimulating hormone (TSH) and with high rates of gestational complications. A low range of preconception TSH is followed by low rates of gestational complications. It is unknown whether TSH levels are elevated in adolescents with PCOS and, if so, whether traditional or exploratory treatments can lower them into safe preconception range. We investigated TSH in non-obese adolescents with PCOS, including the effects of randomized interventions. Methods Morning TSH was a safety marker in randomized pilot studies comparing the effects of an oral contraceptive (OC) versus those of a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) in non-obese adolescents with PCOS. A post-hoc analysis compared: TSH levels in PCOS (N= 62) vs controls; TSH changes on treatment (for 1 year); TSH levels post treatment (for 1 year). Results Mean TSH levels were higher in PCOS patients than in control girls (P

Introduction: Fatty acids are essential nutrients for the fetus and are supplied by the mother through the placenta. Desaturase and elongase enzymes play an important role in modulating the fatty acid composition of body tissues. We aimed to compare the fatty acid profile and the estimated desaturase and elongase activities in the placenta of appropriate (AGA) versus small-for-gestational-age (SGA), and to determine their relationship with the offspring size at birth. Methods: The placental fatty acid profile was analyzed by gas chromatography in 84 infants (45 AGA and 30 SGA) from a prenatal cohort study. The estimated desaturase and elongase activities were calculated from productprecursor fatty acid ratios. Results were associated with maternal (age, body mass index and weight gain during gestation) and neonatal (gestational age, sex, birth weight and birth length) parameters. Results: Differences in placental fatty acid composition between AGA and SGA infants rather than correlations thereof with neonatal parameters were observed. Placentas from SGA infants contained lower levels of omega-3 (ALA, EPA, DPA, and DHA) and high omega-6/omega-3 ratios (AA/DHA and LA/ALA), as well as low elongase (Elovl5) and high desaturase (D9Dn7 and D5Dn6) activity as compared to AGA infants (all p < 0.0001). Discussion: Placentas of AGA and SGA infants differed in fatty acids profile as well as in estimated desaturase and elongase activities. A striking feature of SGA placentas was the low availability of omega-3. Hence, omega-3 fatty acid status deserves further attention, as a potential target of prenatal interventions. This study was supported by grants from the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (ISCIII), Madrid, Spain (PI17/ 00557 and PI19/00451 to JB), projects co-funded by FEDER (Fondo Europeo de Desarrollo Regional).

A prime concern of young patients with Polycystic Ovary Syndrome (PCOS) is the control of body adiposity, given their tendency to gain weight and/or their difficulty to lose weight. Circulating growth-and-differentiation factor-15 (GDF15) facilitates the control of body weight via receptors in the brainstem. C-reactive protein (CRP) and insulin are endogenous GDF15 secretagogues. We hypothesised that PCOS in non-obese adolescents is characterised by low concentrations of circulating GDF15, when judged by the degree of CRP and insulin drive. GDF15 was added as a post-hoc endpoint of two previously reported, randomised studies in non-obese adolescent girls with PCOS (N = 58; 60% normal weight; 40% overweight) who received either an oral oestroprogestogen contraceptive (OC), or a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) for 1 year; subsequently, all girls remained untreated for 1 year. Adolescent girls with regular menses (N = 20) served as healthy controls. Circulating GDF15, CRP and fasting insulin were assessed prior to treatment, and halfway the on- and post-treatment years. Pre-treatment, the absolute GDF15 concentrations were normal in PCOS girls, but their relative levels were markedly low, in view of the augmented CRP and insulin drives. OC treatment was accompanied by a near-doubling of circulating GDF15 (on average, from 296 to 507 pg/mL) and CRP, so that the relative GDF15 levels remained low. SPIOMET treatment was accompanied by a 3.4-fold rise of circulating GDF15 (on average, from 308 to 1045 pg/mL) and by a concomitant lowering of CRP and insulin concentrations towards normal, so that the relative GDF15 levels became markedly abundant. Post-OC, the relatively low GDF15 levels persisted; post-SPIOMET, the circulating concentrations of GDF15, CRP and insulin were all normal. BMI remained stable in both treatment groups. Only SPIOMET was accompanied by a reduction of hepato-visceral fat (by MRI) towards normal. In conclusion, early PCOS was found to be characterised by a relative GDF15 deficit that may partly explain the difficulties that young patients experience to control their body adiposity. This relative GDF15 deficit persisted during and after OC treatment. In contrast, SPIOMET treatment was accompanied by an absolute and a relative abundance of GDF15, and followed by normal GDF15, CRP and insulin concentrations. The present findings strengthen the rationale to raise the concentrations of circulating GDF15 in early PCOS, for example with a SPIOMET-like intervention that attenuates low-grade inflammation, insulin resistance and ectopic adiposity, without necessarily lowering body weight.Clinical trial registries: ISRCTN29234515 and ISRCTN11062950.

Background Pituitary stalk interruption syndrome (PSIS) may associate with brain midline defects and also with polydactyly (GLI2 mutations) but rarely with brain cortex anomalies. Clinical Case We report a boy referred at age 19 months because of growth failure. Bilateral postaxial polydactyly, syndactyly of the toes, and a nodule on the tongue were noted at term birth. The neonatal course was complicated by marked but transient hypoglycemia. During infancy, the acquisition of gross motor skills was slightly delayed. Upon referral, body length was 4.1 SD below the level of mid-parental height. Extremely low concentrations of circulating IGF-I (8 mcg/L) and IGFBP-3 (861 mcg/L) were suggestive of growth hormone (GH) deficiency which was corroborated by glucagon test (peak GH 3.3 mcg/L, peak cortisol 14.6 mcg/dL) in an euthyroid and normoprolactinemic state, and in the absence of polydipsia or polyuria. Brain MRI disclosed not only a PSIS triad (with a virtual absence of the pituitary stalk and the anterior pituitary, and with an ectopic position of the posterior pituitary) but also abnormal sulcation and polymicrogyria (pointing to abnormal lamination in the cortex) on both sides in the posterior cingulum. Familial history is positive for holoprosencephaly and polydactyly in two male relatives, who died neonatally. Whole exome sequencing showed a rare maternally inherited variant in ZRSR2 on the X chromosome (c. 1207_1208delAG (p.Arg403Glyfs*24)) (OMIM 300028). ZRSR2 isdepleted from loss-of-function variants in the reference population, and has not been associated with congenital anomalies or with pituitary dysfunction. This ZRSR2 variant escapes nonsense mediated decay and segregates in this family according to an X-linked recessive pattern. X-inactivation studies and gene expression studies are ongoing to correlate the ZRSR2 variant to the patient's phenotype. Conclusion This case describes a toddler with polydactyly and short stature, based on GH deficiency due to PSIS, in combination with polymicrogyria. Studies are ongoing to link the patient's phenotype to a rare variant in ZRSR2. Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Patients with Turner syndrome (TS), the most common sex chromosome abnormality in women, can suffer from a variety of well-researched reproductive, cardiovascular, metabolic, and autoimmune comorbidities. Few studies investigate the neoplasia risk. We assessed the general neoplasia risk in TS women, and more specifically, the gonadoblastoma/dysgerminoma risk in the subgroup with Y chromosome mosaicism, and evaluated potential risk factors for neoplasia development, such as karyotype, metabolic and autoimmune comorbidity, and treatment with growth hormone and/or estrogen replacement.10-year retrospective cohort study in a tertiary referral centre in Belgium.105 TS women were included (median age 29; range 2-69). Six malignant tumours were detected in 5 (4.8%) patients (SIR = 0.6, 95% CI 0.2-1.0). In addition, 2 benign meningiomas were observed, resulting in 3 (2.9%) tumours of the central nervous system (CNS; SIR = 19.9, 95% CI 4.0-35.8). No breast cancer was noted. Benign neoplasms occurred in 22 women (21.0%), with skin lesions being the most frequent. All patients with Y chromosome mosaicism (n = 9; 8.6%) underwent prophylactic gonadectomy, but gonadoblastoma/dysgerminoma was not detected. A weak association was found between any tumour type and autoimmune comorbidity (r = 0.24; p = 0.02).The overall malignancy risk was not increased, but a different pattern of occurrence is apparent, with an increased risk of CNS and skin tumours and a decreased breast cancer risk. Gonadoblastoma/dysgerminoma was not reported. There is a need for centralised multidisciplinary care and prospective research to unravel and predict the neoplasia risk.

Low birth weight (LBW) followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) plays an important role in the regulation of energy homeostasis, reducing food intake and body weight. We assessed whether GDF15 concentrations are raised by long-term metformin treatment in LBW/catch-up girls with precocious pubarche (PP, pubic hair8 years), and whether they relate to changes in endocrine-metabolic variables, body composition, and abdominal fat partitioning.Circulating GDF15 was determined in 30 LBW/catch-up girls with PP randomly assigned to receive metformin for 4 years (n = 15; 425 mg/d for 2 years, then 850 mg/d for 2 years) or to remain untreated (n = 15). Endocrine-metabolic variables, body composition (by absorptiometry), and abdominal fat partitioning (by MRI) were assessed at the start and yearly during follow-up.Circulating GDF15 concentrations increased significantly in LBW-PP girls only after 3 and 4 years on metformin. GDF15 levels associated negatively with insulin, HOMA-IR, androgens, body fat, and visceral fat.Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with reduced prenatal growth. GDF15 could be among the mediators of such effects, especially over the long term.Low birth weight followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) is a peptide hormone that reduces food intake and lowers body weight; metformin is an exogenous GDF15 secretagogue. Serum GDF15 concentrations increase after 3 and 4 years on metformin and associate negatively with insulin, androgens, body fat, and visceral fat. Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with low birth weight. GDF15 could mediate these effects, especially over the long term.

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 nonshivering 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. Methods 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. The main outcome measures were weight and length Z-scores, total and abdominal fat content (by dual X-ray absorptiometry), 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 = .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. Conclusion 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.

Introduction PCOS in adolescent girls and young women is nowadays thought to be, in essence, an epiphenomenon of ectopic fat accumulation. By definition, "adolescent PCOS" is characterized by androgen excess (as well clinical as biochemical) and oligo-anovulation (often judged by oligo-amenorrhea) (1) presenting between 2 and 8 years after menarche. There is no FDA-approved treatment for "adolescent PCOS". In SPIOMET4HEALTH (a project funded by the European Commission under Grant Agreement 899671), we aim at reducing ectopic fat in an early phase of PCOS, with a standardized lifestyle intervention plus a pharmacological addendum consisting of either placebo, or PIO, or SPIO, or SPIOMET. In "adolescent PCOS", low-dose pioglitazone (7.5 mg/d) may exert insulin-sensitizing and gonadotropin-normalizing effects, in part by raising the circulating concentrations of high-molecular-weight adiponectin; low-dose spironolactone (50 mg/d) may not only act as an anti-androgen but also exert anti-mineralocorticoid effects that raise energy expenditure by activating brown adipose tissue; low-dose metformin (850 mg/d) is known to act through multiple mechanisms and was recently shown to be capable of changing the relative deficit of GDF15 into an abundance that is thought to contribute to reduce liver fat. Subjects & Methods In the SPIOMET4HEALTH trial, patients with "adolescent PCOS" (age range 12. 0–23.9 years; BMI Expected Results/Discussion The SPIOMET4HEALTH project is expected to deliver the first results of an international, randomized, double-blind, active-controlled/placebo-controlled trial evaluating the safety, efficacy, and tolerability of the fixed dose combination SPIOMET in adolescent girls and young women with PCOS. Favorable results of this Phase 2 trial may advance SPIOMET into Phase 3. Reference: Ibáñez L, et al. An International Consortium Update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm Res Paediatr 2017;88: 371-395. Presentation: No date and time listed

Growth-and-differentiation-factor-15 (GDF15) is a regulator of energy homeostasis. To determine the relationship between circulating GDF15 and parameters of metabolic health, we assessed longitudinally GDF15 concentrations in infants born either appropriate- (AGA) or small-for-gestational-age (SGA), the latter population known to be at risk for metabolic alterations, particularly after a rapid postnatal catch-up in weight. The study cohort consisted of 103 infants (70 AGA and 33 SGA). Assessments included body length, weight, and ponderal index (PI); fasting glucose, insulin, IGF-I, high-molecular-weight adiponectin, GDF15; and body composition (by absorptiometry) at birth, and at age 4, 12 and 24 months. GDF15 levels at birth were significantly higher than those at each subsequent time point and were similar in AGA and SGA subjects. GDF15 concentrations dropped at age 4 months, more substantially in SGA infants, and continued to decline in both subgroups reaching adult concentrations by age 24 months. GDF15 levels correlated inversely with the changes in PI, IGF-I and body fat throughout follow-up. Early life is associated with supra-adult concentrations of GDF15. The lower levels of GDF15 in SGA subjects may be an adaptive mechanism to promote catch-up in weight and might increase the risk for obesity later in life.

Background Metformin treatment for 24 months in children with obesity lowers body mass index (BMI), reduces liver fat, and normalizes endocrine-metabolic parameters. Objective Here we study whether circulating GDF-15 levels were raised by such metformin treatment and whether they related to changes in body weight and visceral fat in children with obesity. Methods The study population consisted of 18 pre-pubertal/early pubertal children with obesity who had participated in a randomized double-blind clinical trial receiving metformin (850 mg/day) or placebo for 24 months. Circulating GDF-15, BMI and abdominal visceral and liver fat (magnetic resonance imaging) were assessed at 0, 6, 12 and 24 months. Results Results showed that metformin-treated children had higher GDF-15 levels at 6 and 12 months. Higher rises of circulating GDF-15 associated with more loss of body weight and visceral fat. Conclusion In conclusion, the concept that GDF-15 is among the mediators of metformin's normalizing effects in individuals with obesity is herewith extended into childhood.

Background Children with low birth weight (LBW) have a higher risk of developing endocrine-metabolic disorders later in life. Deregulation of specific microRNAs (miRNAs) could underscore the programming of adult pathologies. We analyzed the miRNA expression pattern in both umbilical cord serum samples from LBW and appropriate-for-gestational-age (AGA) newborns and maternal serum samples in the 3rd trimester of gestation, and delineated the relationships with fetal growth, body composition, and markers of metabolic risk. Methods Serum samples of 12 selected mother-newborn pairs, including 6 LBW and 6 AGA newborns, were used for assessing miRNA profile by RNA-sequencing. The miRNAs with differential expression were validated in a larger cohort [49 maternal samples and 49 umbilical cord samples (24 LBW, 25 AGA)] by RT-qPCR. Anthropometric, endocrine-metabolic markers and body composition (by DXA) in infants were determined longitudinally over 12 months. Results LBW newborns presented reduced circulating concentrations of miR-191-3p (P = 0.015). miR-191-3p levels reliably differentiated LBW from AGA individuals (ROC AUC = 0.76) and were positively associated with anthropometric and body composition measures at birth and weight Z-score at 12 months (P Conclusions miR-191-3p was reliably different in LBW individuals, and could be a new player in the epigenetic mechanisms linking LBW and future endocrine-metabolic adverse outcomes. Impact Children with low birth weight (LBW) have a higher risk of developing endocrine-metabolic disorders. Deregulation of specific microRNAs (miRNAs) could underscore the programming of those pathologies. miR-191-3p is downregulated in serum of LBW newborns, and its concentrations associate positively with neonatal anthropometric measures, with lean mass and bone accretion at age 15 days and with weight Z-score at age 12 months. miR-191-3p was reliably different in individuals with LBW, and could be a new player in the epigenetic mechanisms connecting LBW and future endocrine-metabolic adverse outcomes.

Associations between glomerular filtration rate (GFR) and cardiometabolic risk factors have been reported in adult and pediatric patients with renal disease. We aimed to assess the relationship between the estimated GFR (eGFR) and cardiometabolic risk factors in apparently healthy children. A longitudinal study in 401 asymptomatic Caucasian children (mean age 8 years) followed up after 4 years (mean age 12 years). GFR was estimated using the pediatric form of the FAS-equation. Children were classified at baseline according to their obesity status (normal weight and overweight) and according to eGFR levels (lower, average, and higher). The association of eGFR with anthropometric data [body mass index (BMI) and waist], blood pressure [systolic (SBP) and diastolic (DBP)], metabolic parameters [glucose, insulin resistance (HOMA-IR) and serum lipids], and renal ultrasonography measurements were assessed at baseline and follow-up. Baseline eGFR associated with several cardiometabolic risk factors at follow-up including higher waist, SBP, HOMA-IR, and kidney size (all p

Maternal overfeeding during gestation may lead to adverse metabolic programming in the offspring mediated by epigenetic alterations. Potential reversal, in early life, of these alterations may help in the prevention of future cardio-metabolic conditions. In this context, our aims were: (1) to study the effects of maternal overfeeding on the metabolic and epigenetic programming of offspring's adipose tissue; and (2) to test the potential of postnatal metformin treatment to reverse these changes.We used a swine animal model where commercial production sows were either overfed or kept under standard diet during gestation, and piglets at birth were randomly assigned to metformin (n = 16 per group) or vehicle treatment during lactation (n = 16 per group).Piglets born to overfed sows showed a worse metabolic profile (higher weight, weight gain from birth and abdominal circumference; all p 0.05) together with altered serological markers (increased HOMA-IR, fructosamine, total cholesterol, C-Reactive Protein and lower HMW adiponectin; all p 0.05). The visceral adipose tissue also showed altered morphology (increased adipocyte area, perimeter and diameter; all p 0.05), as well as changes in gene expression (higher CCL2 and INSR, lower DLK1; all p 0.05), and in DNA methylation (96 hypermethylated and 99 hypomethylated CpG sites; FDR 0.05). Metformin treatment significantly ameliorated the abnormal metabolic profile, decreasing piglets' weight, weight gain from birth, abdominal circumference and fructosamine (all p 0.05) and reduced adipocyte area, perimeter, and diameter in visceral adipose tissue (all p 0.05). In addition, metformin treatment potentiated several associations between gene expression in visceral adipose tissue and the altered metabolic markers.Maternal overfeeding during gestation leads to metabolic abnormalities in the offspring, including adipose tissue alterations. Early metformin treatment mitigates these effects and could help rescue the offspring's metabolic health.

Background Diazepam-binding inhibitor (DBI) controls feeding behaviour and glucose homeostasis. Individuals born small-for-gestational-age (SGA) with excessive postnatal catch-up in weight are at risk for obesity and type 2 diabetes. Objective To assess serum concentrations of DBI (0-2 years) in appropriate-for-gestational-age (AGA, n = 70) vs SGA infants (n = 33) with spontaneous catch-up and their relationship with endocrine-metabolic and adiposity markers. Methods Longitudinal assessments included auxology, fasting glucose, insulin, insulin-like growth factor, high-molecular-weight adiponectin, DBI and body composition (absorptiometry). DBI was measured cross-sectionally in pregnant and non-pregnant women and in 2-day-old newborns. DBI mRNA expression levels were assessed in adult and neonatal tissues. Results Cord blood DBI concentrations were similar in AGA and SGA newborns and about fivefold higher than those in women. Serum DBI levels decreased by age 2 days, were higher in SGA vs AGA infants at age 2 years and associated negatively with markers of adiposity and insulin resistance and positively with high-molecular-weight adiponectin. DBI mRNA expression was lower in placenta than in other tissues. Conclusion The increased DBI concentrations at birth are unrelated to prenatal growth. The higher DBI levels in SGA subjects at age 2 years may be related to catch-up growth or represent an adaptive mechanism to promote lipogenesis.

BACKGROUND: Accelerated catch-up growth following intrauterine restriction increases the risk of developing visceral adiposity and metabolic abnormalities. However, the underlying molecular mechanisms of such metabolic programming are still poorly understood. METHODS: A Wistar rat model of catch-up growth following intrauterine restriction was used. A gene expression array was performed in the retroperitoneal adipose tissue sampled at postnatal day (PD) 42. RESULTS: Five hundred and forty-six differentially expressed genes (DEGs) were identified (adjusted p value

Adolescent polycystic ovary syndrome (PCOS) is most often the outcome of a mismatch between an energy-sparing (epi)genetic background and a relatively energy-rich environment. This mismatch results in a sustained requirement to store more fat than is safely feasible in subcutaneous adipose tissue, and the excess of fat ends up being stored in ectopic depots, notably in the liver and viscera (= hepato-visceral or central fat). In adolescent girls with PCOS, prolonged treatment with an estro-progestagen contraceptive reduces the androgen excess but not the underpinning PCOS drive (exerted by ectopic fat excess and insulin resistance) so that, upon discontinuation of such prolonged treatment, the young women rebound swiftly into androgen excess and oligo-anovulation, thus into adult PCOS.

IntroductionPrenatal growth restraint followed by rapid postnatal weight gain increases lifelong diabetes risk. Epigenetic dysregulation in critical windows could exert long-term effects on metabolism and confer such risk.Research design and methodsWe conducted a genome-wide DNA methylation profiling in peripheral blood from infants born appropriate-for-gestational-age (AGA, n=30) or small-for-gestational-age (SGA, n=21, with postnatal catch-up) at age 12 months, to identify new genes that may predispose to metabolic dysfunction. Candidate genes were validated by bisulfite pyrosequencing in the entire cohort. All infants were followed since birth; cord blood methylation profiling was previously reported. Endocrine-metabolic variables and body composition (dual-energy X-ray absorptiometry) were assessed at birth and at 12 and 24 months.ResultsGPR120 (cg14582356, cg01272400, cg23654127, cg03629447), NKX6.1 (cg22598426, cg07688460, cg17444738, cg12076463, cg10457539), CPT1A (cg14073497, cg00941258, cg12778395) and IGFBP 4 (cg15471812) genes were hypermethylated (GPR120, NKX6.1 were also hypermethylated in cord blood), whereas CHGA (cg13332653, cg15480367, cg05700406), FABP5 (cg00696973, cg10563714, cg16128701), CTRP1 (cg19231170, cg19472078, cg0164309, cg07162665, cg17758081, cg18996910, cg06709009), GAS6 (N/A), ONECUT1 (cg14217069, cg02061705, cg26158897, cg06657050, cg15446043) and SLC2A8 (cg20758474, cg19021975, cg11312566, cg12281690, cg04016166, cg03804985) genes were hypomethylated in SGA infants. These genes were related to β-cell development and function, inflammation, and glucose and lipid metabolism and associated with body mass index, body composition, and markers of insulin resistance at 12 and 24 months.ConclusionIn conclusion, at 12 months, abnormal methylation of GPR120 and NKX6.1 persists and new epigenetic marks further involved in adipogenesis and energy homeostasis arise in SGA infants. These abnormalities may contribute to metabolic dysfunction and diabetes risk later in life.

Background Circulating growth-differentiation factor-15 (GDF15), a cellular stress marker, abruptly increases during critical illness, but its later time course remains unclear. GDF15 physiologically controls oral intake by driving aversive responses to nutrition. Early parenteral nutrition (PN) in ICU patients has overall been shown not beneficial. We hypothesized that low GDF15 can identify patients who benefit from early PN, tolerate enteral nutrition (EN), and resume spontaneous oral intake. Methods In secondary analyses of the EPaNIC-RCT on timing of PN initiation (early PN versus late PN) and the prospective observational DAS study, we documented the time course of circulating GDF15 in ICU (N = 1128) and 1 week post-ICU (N = 72), compared with healthy subjects (N = 65), and the impact hereon of randomization to early PN versus late PN in propensity score-matched groups (N = 564/group). Interaction between upon-admission GDF15 and randomization for its outcome effects was investigated (N = 4393). Finally, association between GDF15 and EN tolerance in ICU (N = 1383) and oral intake beyond ICU discharge (N = 72) was studied. Results GDF15 was elevated throughout ICU stay, similarly in early PN and late PN patients, and remained high beyond ICU discharge (p p ≤ 0.002). Lower GDF15 was only weakly related to gastrointestinal tolerance (p p = 0.05). Conclusion In critically ill patients, high GDF15 reflected poor prognosis and may contribute to aversive responses to nutrition. However, the potential of GDF15 as “ready-to-feed indicator” appears limited. Trial registration ClinicalTrials.gov, NCT00512122, registered 31 July 2007, https://www.clinicaltrials.gov/ct2/show/NCT00512122 (EPaNIC trial) and ISRCTN, ISRCTN 98806770, registered 11 November 2014, http://www.isrctn.com/ISRCTN98806770 (DAS trial)

STUDY QUESTION Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control? SUMMARY ANSWER In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely pathogenic (epi)genetic defects were identified in 12 (33%) patients, providing insights into the genetics of human pubertal control. WHAT IS KNOWN ALREADY A few studies have described patients with CPP associated with multiple anomalies, but without making inferences on causalities of CPP. Genetic-molecular studies of syndromic cases may reveal disease genes or mechanisms, as the presentation of such patients likely indicates a genetic disorder. STUDY DESIGN, SIZE, DURATION This translational study was based on a genetic-molecular analysis, including genome-wide high throughput methodologies, for searching structural or sequence variants implicated in CPP and DNA methylation analysis of candidate regions. PARTICIPANTS/MATERIALS, SETTING, METHODS A cohort of 197 patients (188 girls) with CPP without structural brain lesions was submitted to a detailed clinical evaluation, allowing the selection of 36 unrelated patients (32 girls) with CPP associated with multiple anomalies. Pathogenic allelic variants of genes known to cause monogenic CPP (KISS1R, KISS1, MKRN3 and DLK1) had been excluded in the entire cohort (197 patients). All selected patients with CPP associated with multiple anomalies (n = 36) underwent methylation analysis of candidate regions and chromosomal microarray analysis. A subset (n = 9) underwent whole-exome sequencing, due to presenting familial CPP and/or severe congenital malformations and neurocognitive abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE Among the 36 selected patients with CPP, the more prevalent associated anomalies were metabolic, growth and neurocognitive conditions. In 12 (33%) of them, rare genetic abnormalities were identified: six patients presented genetic defects in loci known to be involved with CPP (14q32.2 and 7q11.23), whereas the other six presented defects in candidate genes or regions. In detail, three patients presented hypomethylation of DLK1/MEG3:IG-DMR (14q32.2 disruption or Temple syndrome), resulting from epimutation (n = 1) or maternal uniparental disomy of chromosome 14 (n = 2). Seven patients presented pathogenic copy number variants: three with de novo 7q11.23 deletions (Williams–Beuren syndrome), three with inherited Xp22.33 deletions, and one with de novo 1p31.3 duplication. Exome sequencing revealed potential pathogenic variants in two patients: a sporadic female case with frameshift variants in TNRC6B and AREL1 and a familial male case with a missense substitution in UGT2B4 and a frameshift deletion in MKKS. LIMITATIONS, REASONS FOR CAUTION The selection of patients was based on a retrospective clinical characterization, lacking a longitudinal inclusion of consecutive patients. In addition, future studies are needed, showing the long-term (mainly reproductive) outcomes in the included patients, as most of them are not in adult life yet. WIDER IMPLICATIONS OF THE FINDINGS The results highlighted the relevance of an integrative clinical-genetic approach in the elucidation of mechanisms and factors involved in pubertal control. Chromosome 14q32.2 disruption indicated the loss of imprinting of DLK1 as a probable mechanism of CPP. Two other chromosomal regions (7q11.23 and Xp22.33) represented new candidate loci potentially involved in this disorder of pubertal timing. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grant number 2018/03198-0 (to A.P.M.C.) and grant number 2013/08028-1 (to A.C.V.K) from the São Paulo Research Foundation (FAPESP), and grant number 403525/2016-0 (to A.C.L.) and grant number 302849/2015-7 (to A.C.L.) and grant number 141625/2016-3 (to A.C.V.K) from the National Council for Scientific and Technological Development (CNPq). The authors have nothing to disclose. TRIAL REGISTRATION NUMBER N/A.

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