Dlk1 expression relates to visceral fat expansion and insulin resistance in male and female rats with postnatal catch-up growth

Background: Although prenatal and postnatal programming of metabolic diseases in adulthood is well established, the mechanims underpinning metabolic programming are not. DLK1, a key regulator of fetal development, inhibits adipocyte differentiation and restricts fetal growth. Methods: Assess Dlk1 expression in Wistar rat model of catch-up growth following intrauterine restriction. Dams fed ad libitum deliverd control pups (C) and dams on a 50% calorie-restricted diet delivered pups with low birth weight (R). Restricted offspring fed a standard rat chow showd catch-up growth (R/C) but those kept on a calorie-restricted diet did not (R/R). Results: Decreased Dlk1 expression was observed in adipose tissue and skeletal muscle of R/C pups along with excessive visceral fat accumulation, decreased circulating adiponectin, increased triglycerides and HOMA-IR (from p<0.05 to p<0.001). Moreover, in R/C pups, the reduced Dlk1 expression in adipose tissue and skeletal muscle correlated with visceral fat (r= -0.820; p<0.0001) and HOMA-IR (r= -0.745; p=0.002). Conclusions: Decreased Dlk1 expression relates to visceral fat expansion and insulin resistance in a rat model of catch-up growth following prenatal growth restriction. Modulation of Dlk1 expression could be among the targets of the early prevention of fetal preogramming of adult metabolic disorders

Circulating fatty acid synthase in pregnant women: relationship to blood pressure, maternal metabolism and newborn parameters.

The enzyme FASN (fatty acid synthase) is potentially related with hypertension and metabolic dysfunction. FASN is highly expressed in the human placenta. We aimed to investigate the relationship circulating FASN has with blood pressure, maternal metabolism and newborn parameters in healthy pregnant women. Circulating FASN was assessed in 115 asymptomatic pregnant women in the second trimester of gestation along with C-peptide, fasting glucose and insulin, post-load glucose lipids, HMW-adiponectin and blood pressure (the latter was assessed in each trimester of gestation). At birth, newborns and placentas were weighed. FASN expression was also able to be assessed in 80 placentas. Higher circulating FASN was associated with lower systolic blood pressure (SBP), with a more favourable metabolic phenotype (lower fasting glucose and insulin, post load glucose, HbAc1, HOMA-IR and C-peptide), and with lower placental and birth weight (all p < 0.05 to p < 0.001). Placental FASN expression related positively to circulating FASN (p < 0.005) and negatively to placental weight (p < 0.05). Our observations suggest a physiological role of placental FASN in human pregnancy. Future studies will clarify whether circulating FASN of placental origin does actually regulate placental and fetal growth, and (thereby) has a favourable influence on the pregnant mother's insulin sensitivity and blood pressure

Serum alkaline phosphatase relates to cardiovascular risk markers in children with high calcium-phosphorus product

Although alkaline phosphatase (ALP) correlates with cardiovascular risk in adults, there are no studies in children. We evaluated the association between serum ALP levels, calcium-phosphorus product (Ca*P) and cardiovascular risk markers in healthy children. Children aged 7.9 ± 1.4 (n = 379) were recruited in this cross-sectional study. The main outcome measures were systolic and diastolic blood pressure (SBP and DBP) and carotid intima-media thickness (cIMT). Additional assessments were body-mass index (BMI), waist circumference, homeostatic model assessment of insulin resistance (HOMA-IR) and fasting lipids, ALP, serum calcium, phosphorus and Ca*P. ALP was directly correlated with BMI (p < 0.0001), waist circumference (p < 0.0001), SBP (p < 0.0001), cIMT (p = 0.005), HOMA-IR (p < 0.0001), and fasting triglycerides (p = 0.0001). Among them, in children with Ca*P values above the median the associations were BMI (r = 0.231; p = 0.001), waist (r = 0.252; p < 0.0001), SBP (r = 0.324; p < 0.0001), cIMT (r = 0.248; p = 0.001) and HOMA-IR (r = 0.291; p < 0.0001)]. ALP independently associated with SBP (β = 0.290, p < 0.001) and cIMT (β = 0.179, p = 0.013) in children with higher Ca*P, after adjusting for confounding variables. Circulating ALP is associated with a more adverse cardiovascular profile in children with higher Ca*P. We suggest that serum ALP and Ca*P levels could contribute to the assessment of risk for cardiovascular disease in children

Catch-up growth in juvenile rats, fat expansion, and dysregulation of visceral adipose tissue

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 < 0.05). Gene ontology enrichment analysis identified pathways related to immune and lipid metabolic processes, brown fat cell differentiation, and regulation of PI3K. Ccl21, Npr3, Serpina3n, Pnpla3, Slc2a4, and Serpina12 were validated to be upregulated in catch-up pups (all p < 0.01) and related to several fat expansion and metabolic parameters, including body weight at PD42, postnatal body weight gain, white and brown adipose tissue mass, plasma triglycerides, and insulin resistance index (all p < 0.05). CONCLUSIONS: Genes related to immune and metabolic processes were upregulated in retroperitoneal adipose tissue following catch-up growth in juvenile rats and were found to be associated with fat expansion and metabolic parameters. Our results provide evidence for several dysregulated genes in white adipose tissue that could help develop novel strategies to prevent the metabolic abnormalities associated with catch-up growth

Methylation of the C19MC microRNA locus in the placenta: association with maternal and chilhood body size.

OBJECTIVES: To study DNA methylation at the C19MC locus in the placenta and its association with (1) parental body size, (2) transmission of haplotypes for the C19MC rs55765443 SNP, and (3) offspring's body size and/or body composition at birth and in childhood. SUBJECTS AND METHODS: Seventy-two pregnant women-infant pairs and 63 fathers were included in the study. Weight and height of mothers, fathers and newborns were registered during pregnancy or at birth (n = 72). Placental DNA methylation at the C19MC imprinting control region (ICR) was quantified by bisulfite pyrosequencing. Genotyping of the SNP was performed using restriction fragment length polymorphisms. The children's body size and composition were reassessed at age 6 years (n = 32). RESULTS: Lower levels of placental C19MC methylation were associated with increased body size of mother, specifically with higher pregestational and predelivery weights and height of the mother (β from -0.294 to -0.371; R2 from 0.04 to 0.10 and all p < 0.019), and with higher weight, height, waist and hip circumferences, and fat mass of the child (β from -0.428 to -0.552; R2 from 0.33 to 0.56 and all p < 0.009). Parental transmission of the SNP did not correlate with an altered placental methylation status at the C19MC ICR. CONCLUSIONS: Increased maternal size is associated with reduced placental C19MC methylation, which, in turn, relate to larger body size of the child.This study was supported by grants from the Ministerio de Ciencia e Innovación, Instituto de 10 Salud Carlos III (ISCIII), Madrid, Spain (PI17/00557 to JB, and PI13/01257 and PI16/01335 to AL-B), projects co-funded by FEDER (Fondo Europeo de Desarrollo Regional). RF and MG acknowledge grant funding from the Fondation pour la Recherche Médicale (Equipes FRM, 13 grant number DEQ31703)

Renal size and cardiovascular risk in prepubertal children

Renal size is an important parameter for the evaluation and diagnosis of kidney disease and has been associated with several cardiovascular risk factors in patients with kidney failure. These results are however discordant and studies in healthy children are lacking. We aimed to study the association between renal size (length and volume) and cardiovascular risk parameters in healthy children. Clinical, analytical and ultrasound parameters [renal length, renal volume, perirenal fat and carotid intima-media thickness (cIMT)] were determined in 515 healthy prepubertal children (176 lean, 208 overweight and 131 obese). Renal length and volume associated significantly and positively with several anthropometric and cardiovascular risk parameters including cIMT and systolic blood pressure (SBP) (all p < 0.001). Renal length and volume associated with cIMT and SBP in all study subgroups, but these associations were predominant in obese children, in whom these associations were independent after adjusting for age, gender and BSA (all p < 0.05). In multivariate analyses in the study subjects as a whole, renal length was an independent predictor of cIMT (β = 0.310, p < 0.0001) and SBP (β = 0.116, p = 0.03). Renal size associates with cIMT and SBP, independent of other well-established cardiovascular risk factors, and may represent helpful parameters for the early assessment of cardiovascular risk in children

Salivary cardiac-enriched FHL2-interacting protein is associated with higher diastolic-to-systolic-blood pressure ratio, sedentary time and center of pressure displacement in healthy 7-9 years old school-children

IntroductionCardiac-enriched FHL2-interacting protein (CEFIP) is a recently identified protein, first found in the z-disc of striated muscles, and related to cardiovascular diseases. Our objectives are: 1) to quantify CEFIP in saliva in healthy 7-9 years old school-children; and 2) to assess the associations of salivary CEFIP concentration and blood pressure, physical (in)activity and physical fitness in these children.MethodsA total of 72 children (7.6 ± 0.3 years) were included in the study, recruited in primary schools in Girona (Spain). A sandwich enzyme-linked immunosorbent assay was used (abx506878; Abbexa, United Kingdom) to quantify CEFIP in saliva. Anthropometric evaluation was performed [body mass, height and body mass index (BMI)]. Systolic and diastolic blood pressure were measured by means of an electronic oscillometer and the diastolic-to-systolic blood pressure ratio (D/S BP ratio) was calculated. Physical (in)activity [sedentary time and time spent in physical activity (PA)] were assessed by means of a triaxial Actigraph GT3X accelerometer (Actigraph, Pensacola, FL, USA) that children were instructed to wear for 24h during 7 conssecutive days. Finally, physical fitness (speed and agility, explosive power of legs, handgrip strength, flexibility and balance) were assessed through validated and standardized testing batteries.ResultsCEFIP was easily detected and measured in all saliva samples (mean concentration: 0.6 ± 0.2 pg/ml). Salivary CEFIP was positively associated with D/S BP ratio (r=0.305, p=0.010) and sedentary time (r=0.317, p=0.012), but negatively associated with PA in 7-9 years old school-children (r=-0.350, p=0.002). Furthermore, salivary CEFIP was related to lower level of balance i.e., higher center of pressure (CoP) displacement in these children (r=0.411, p&lt;0.001). The associations of salivary CEFIP with D/S BP ratio (Beta=0.349, p=0.004), sedentary time (Beta=0.354, p=0.009) and CoP displacement (Beta=0.401, p=0.001), were maintained significant after adjustment for potential confounding variables such as age, gender and BMI in linear regression analyses.ConclusionCEFIP can be easily assessed in saliva as a promising biomarker associated with cardiovascular health in 7-9 years old school-children. Interestingly, higher salivary CEFIP concentration was related to higher D/S BP ratio, more sedentary time and higher CoP displacement i.e., lower level of balance in these children

Metabolically Healthy Obesity and High Carotid Intima-Media Thickness in Children and Adolescents: International Childhood Vascular Structure Evaluation Consortium

OBJECTIVE It has been argued that metabolically healthy obesity (MHO) does not increase cardiovascular disease (CVD) risk. This study examines the association of MHO with carotid intima-media thickness (cIMT), a proxy of CVD risk, in children and adolescents. RESEARCH DESIGN AND METHODS Data were available for 3,497 children and adolescents aged 6–17 years from five population-based cross-sectional studies in Brazil, China, Greece, Italy, and Spain. Weight status categories (normal, overweight, and obese) were defined using BMI cutoffs from the International Obesity Task Force. Metabolic status (defined as "healthy" [no risk factors] or "unhealthy" [one or more risk factors]) was based on four CVD risk factors: elevated blood pressure, elevated triglyceride levels, reduced HDL cholesterol, and elevated fasting glucose. High cIMT was defined as cIMT ≥90th percentile for sex, age, and study population. Logistic regression model was used to examine the association of weight and metabolic status with high cIMT, with adjustment for sex, age, race/ethnicity, and study center. RESULTS In comparison with metabolically healthy normal weight, odds ratios (ORs) for high cIMT were 2.29 (95% CI 1.58–3.32) for metabolically healthy overweight and 3.91 (2.46–6.21) for MHO. ORs for high cIMT were 1.44 (1.03–2.02) for unhealthy normal weight, 3.49 (2.51–4.85) for unhealthy overweight, and 6.96 (5.05–9.61) for unhealthy obesity. CONCLUSIONS Among children and adolescents, cIMT was higher for both MHO and metabolically healthy overweight compared with metabolically healthy normal weight. Our findings reinforce the need for weight control in children and adolescents irrespective of their metabolic status