Serum 25-hydroxyvitamin D and cardiovascular disease risk factors in women with excessive weight gain during pregnancy and in their offspring at age 5-6 years.

BACKGROUND/OBJECTIVE: Low 25-hydroxyvitamin D levels [25(OH)D] may increase the risk for cardiovascular disease (CVD). In pregnant women excessive weight gain and 25(OH)D deficiency are common complications and both could have deleterious consequences on their children. We aimed to study the relationship between serum 25(OH)D and CVD risk factors in pregnant women and in their offspring at school age. SUBJECTS/METHODS: Fasting serum 25(OH)D and its bioavailable fraction were quantified in 310 healthy pregnant women [with adequate (n = 113), insufficient (n = 113) and excessive (n = 84) weight gain]. A follow-up at 5-6 years was performed in sixty-six children born of these mothers. Lipids, insulin, glucose, and high-sensitivity C-reactive protein (hsCRP) were measured in all subjects. Children's carotid intima-media thickness (cIMT) together with visceral and intra-abdominal fat were measured by ultrasonography. RESULTS: Lower maternal 25(OH)D concentrations were associated with lower maternal age, and higher body mass index, triglycerides and hsCRP (all p < 0.05). In women with excessive weight gain during gestation, serum 25(OH)D concentrations showed independent associations with maternal hsCRP (ß = -0.283 p = 0.03) and triglycerides (ß = -0.436, p = 0.005). Maternal serum 25(OH)D concentrations were also independently associated with cIMT (ß = -0.288, p = 0.04), visceral fat (ß = -0.281, p = 0.01) and intra-abdominal fat (ß = -0.248, p = 0.01) in their children at 5-6 years. CONCLUSIONS: Lower serum 25(OH)D concentrations were related to CVD risk factors in pregnant woman and in their offspring. The cardiometabolic consequences of low 25(OH)D concentrations during pregnancy could be aggravated by excessive weight gain during gestation.

Soluble CRTC3: A Newly Identified Protein Released by Adipose Tissue That Is Associated with Childhood Obesity.

BACKGROUND: CREB-regulated transcription coactivator 3 (CRTC3) is found in adipocytes, where it may promote obesity through disruption of catecholamine signaling. We wished to assess whether CRTC3 is a soluble protein secreted by adipose tissue, explore whether CRTC3 is detectable and quantifiable in the circulation, and ascertain whether CRTC3 serum concentrations are related to metabolic markers in children. METHODS: Explants of adipose tissue from 12 children were cultured to study adipocyte cell size and the secretion of CRTC3 (immunoblot and ELISA). We also performed a cross-sectional and longitudinal study in 211 asymptomatic prepubertal white children at age 7 years, 115 of whom were followed up at age approximately 10 years. We measured circulating concentrations of CRTC3 and studied associations between serum CRTC3 and metabolic markers. RESULTS: Measurable concentrations of CRTC3 were found in conditioned media of adipose tissue explants and in serum samples. CRTC3 concentrations in visceral adipose tissue were negatively associated with adipocyte cell size and positively related to adipocyte cell number (P < 0.05). In the cross-sectional study, higher CRTC3 concentrations were associated with higher body mass index (P = 0.001), waist circumference (P = 0.003), and systolic blood pressure (P = 0.007) and lower high molecular weight adiponectin (P = 0.003). In the longitudinal study, serum concentrations of CRTC3 at age approximately 7 years were associated with changes in waist circumference (ß = 0.254; P = 0.004; r = 0.145) and high molecular weight adiponectin (ß=-0.271; P = 0.014; r = 0.101), respectively, at age approximately 10 years. CONCLUSIONS: CRTC3, a newly identified protein that is related to childhood obesity, is present in the circulation, partly as a result of adipose tissue secretion. Higher serum CRTC3 concentrations are related to and predict a poorer metabolic profile in children.

Balanced duo of anti-inflammatory SFRP5 and proinflammatory WNT5A in children.

BACKGROUND: Secreted frizzled-related protein 5 (SFRP5) is an adipokine protecting against obesity-related insulin resistance and diabetes. SFRP5 binds to wingless type mouse mammary tumor virus (MMTV) integration site family member 5A (WNT5A) to improve insulin sensitivity. We performed the first study of SFRP5 and WNT5A simultaneously in children. METHODS: Prepubertal children (n = 342) were assessed for circulating SFRP5 (all subjects) and circulating WNT5A (210 subjects), and associations were sought with metabolic markers. In conditioned media of adipose tissue explants from 12 additional children, SFRP5 and WNT5A were studied further. RESULTS: The concentrations of SFRP5 and WNT5A correlated positively in serum and in conditioned media (all P < 0.001). Lower level of circulating SFRP5 (lowest quartile) was associated with higher BMI (15% increase, P < 0.0001) and lower level of high-molecular-weight adiponectin (26% decrease, P = 0.002). Circulating WNT5A related closely with insulin resistance assessed by the homeostasis model assessment for insulin resistance and hepatic markers (alanine transaminase and gamma glutamyl transpeptidase), particularly in children with lower circulating SFRP5 levels (all P < 0.004). CONCLUSION: SFRP5 and WNT5A comprise a balanced duo that may regulate metabolic homeostasis in prepubertal children.

Carotid intima-media thickness at 7 years of age: relationship to C-reactive protein rather than adiposity.

OBJECTIVE: According to the concept of adipose tissue expandability, the vascular complications of obesity are related less to the amount of stored fat than to the low-grade inflammation that excess fat storage may elicit. We tested this concept in 7-year-old children by assessing whether carotid intima-media thickness (cIMT) is related to obesity measures or to circulating highly sensitive C-reactive protein (hsCRP), as a marker of low-grade inflammation. STUDY DESIGN: The study group comprised 135 asymptomatic Caucasian children (72 girls and 63 boys; mean age, 7.1±1.1 years) with normal height and weight distributions. Relationships were assessed among cIMT, hsCRP, obesity measures (ie, body mass index [BMI], total fat by bioelectric impedance, and visceral fat by ultrasound), insulin resistance (by the homeostasis model assessment for insulin resistance), and fasting serum lipid levels. RESULTS: cIMT was correlated with hsCRP, but not with BMI or body fat; the regression coefficients between cIMT and hsCRP (adjusted for age, sex, BMI, body fat, and serum lipid levels) were fairly similar across all BMI categories (ß=0.370-0.411; all P<.001 to<.0001). Serum hsCRP increased with increasing BMI, total fat, and visceral fat (all P<.001). CONCLUSION: At age 7 years, cIMT is already associated with low-grade inflammation, as measured by hsCRP, but not with BMI or body fat. These findings imply that public health strategies aimed at early prevention of cardiovascular disease may need to target low-grade inflammation rather than only BMI or adiposity.

Physiological concentrations of serum cortisol are related to vascular risk markers in prepubertal children.

There is increasing evidence that cortisol contributes to cardiovascular risk. It is unclear whether physiological concentrations of serum cortisol are related to vascular risk markers in children. The cross-sectional associations between morning serum cortisol and cardiovascular risk markers: blood pressure (BP) and carotid intima-media thickness (IMT), were examined in a sample of healthy prepubertal children (age, 6.8 ± 0.1 y) attending primary care clinics. Serum cortisol was associated with increased systolic BP (SBP; n = 223; p < 0.001) and carotid IMT (n = 91; p < 0.0001). These associations were independent from age, BMI, body fat, waist, insulin resistance, serum lipids, and heart rate (HR). No gender interactions were apparent in these associations. In summary, a higher morning serum cortisol within the physiological range is in prepubertal children associated with vascular risk markers. Because childhood risk factors predict adult risk for cardiovascular disease, these observations may have implications in the prevention of cardiovascular disease early in life.

Undercarboxylated osteocalcin relates to cardiovascular risk markers in offspring of families with metabolic syndrome.

BACKGROUND: The undercarboxylated form of osteocalcin (ucOC) is an emerging marker of cardiovascular disease. It is unknown if ucOC in related to common cardiovascular risk markers in children. In offspring of families with and without metabolic syndrome (MetS+ and MetS- families), we assessed whether ucOC was related to a continuous metabolic syndrome score (MetS score) and to carotid intima-media thickness (cIMT). METHODS: ucOC and total OC, MetS score and cIMT were assessed in 203 asymptomatic prepubertal children (age 7.6 ± 0.1 yr; 49% girls), of whom 99 were from MetS+ families. RESULTS: In children from MetS+ families, percent ucOC was higher than in children from MetS- families (p < 0.01). In offspring from MetS+ families, higher ucOC and especially higher percent ucOC was independently associated with both the MetS score and cIMT (both p ≤ 0.01). CONCLUSIONS: The undercarboxylated form of OC is related to common cardiovascular risk markers in children at risk for cardiovascular disease.

A common gene variant in STK11 is associated with metabolic risk markers and diabetes during gestation.

OBJECTIVE: To assess whether the common rs8111699 (C528G) variant in STK11 is related to metabolic risk markers in pregnant women and to gestational diabetes mellitus (GDM). DESIGN: Cross-sectional study. SETTING: Hospital. PATIENT(S): A total of 561 pregnant women: 318 without and 243 with GDM (National Diabetes Data Group criteria). INTERVENTION(S): None. MAIN OUTCOME MEASURES(S): rs8111699 variant in STK11 (Taqman technology). Fasting glucose, insulin (homeostatic model assessment of insulin resistance and ß-cell function [HOMA-IR and -ß]) and C-peptide assessed at 24-28 weeks' gestation. RESULT(S): In non-GDM women, the G allele in rs8111699 was associated with lower HOMA-IR (CC: 1.3 ± 0.1 mIU/L; GG: 0.9 ± 0.1 mIU/L) and HOMA-ß (CC: 165 ± 20 mIU/L; GG: 118 ± 10 mIU/L). In GDM women, the G allele was related to lower body mass index (BMI; CC: 27.9 ± 1.0 kg/m(2); GG: 24.5 ± 0.6 kg/m(2)) and C-peptide (CC: 2.3 ± 0.1 ng/mL; GG: 1.6 ± 0.1 ng/mL). The GG genotype was less frequently observed in GDM women (18% vs. 26%), particularly in heavier GDM women (BMI > median: 14% vs. 28%). CONCLUSION(S): In pregnant women, the G allele for the rs8111699 variant in STK11 is associated with a more favorable metabolic phenotype and may protect against the development of GDM, particularly in heavier women.

Relative hypoadiponectinemia, insulin resistance, and increased visceral fat in euthyroid prepubertal girls with low-normal serum free thyroxine.

A lower activity of the thyroid axis within the clinical reference range is related to a dysmetabolic phenotype in adult populations. We posited that such an association is already present as early as in prepubertal childhood. Serum thyroid stimulating hormone (TSH) and free T4, body fat (bioelectric impedance), insulin resistance (homeostasis model assessment of insulin resistance (HOMA(IR))), total and high molecular weight (HMW)-adiponectin and serum lipids were assessed in 234 euthyroid prepubertal children (113 boys and 121 girls) attending primary care clinics. Visceral fat (abdominal ultrasound) was measured in a subset of these subjects (n = 147; 74 boys and 73 girls). Explants of visceral adipose tissue from an additional six prepubertal children (three boys and three girls) were used to study the regulation of total and HMW-adiponectin by thyroid hormone. Serum free T4 was in girls independently associated with HMW-adiponectin, HOMA(IR) and visceral fat, so that circulating HMW-adiponectin decreased by 30% (ß = 0.305 P < 0.005, R(2) = 0.13) and HOMA(IR) and visceral fat increased, respectively, by 90% (ß = -0.255 P < 0.01, R(2) = 0.05) and 30% (ß = -0.369, P < 0.005, R(2) = 0.12) from the highest to the lowest tertile of serum free T4. Nonsignificant differences in these parameters were found in boys. Treatment of visceral fat explants with thyroid hormone increased total and HMW-adiponectin by 70% and 53%, respectively, above control values (P < 0.01). In conclusion, a dysmetabolic phenotype, consisting of relative hypoadiponectinemia, insulin resistance and increased visceral fat, is associated with low-normal serum free thyroxine in euthyroid prepubertal girls. These associations may be partly explained by a positive regulation of HMW-adiponectin secretion by thyroid hormone.

Toward an early marker of metabolic dysfunction: omentin-1 in prepubertal children.

Omentin-1 is a recently recognized adipokine primarily originating in visceral adipose tissue. We posited that circulating omentin-1 could be an early marker of metabolic dysfunction. To this end, we examined the associations between circulating omentin-1, body fat (bioelectric impedance), an endocrine-metabolic profile (homeostasis model assessment for insulin resistance (HOMA(IR)), serum lipids, high-molecular-weight (HMW) adiponectin and blood pressure (BP)) and family history of obesity and diabetes in asymptomatic prepubertal children (n = 161; 77 boys and 84 girls; age 7 ± 1 year) with a normal distribution of height and weight. Increased circulating omentin-1 was associated with a poorer metabolic profile, with relatively higher HOMA(IR), fasting triacylglycerol, BP and familial prevalence of diabetes (all P < 0.005 to P < 0.0001), and relatively lower fraction of HMW adiponectin (P < 0.005), whereas no relationship was found with body weight or fat or with family history of obesity. All these associations were independent of age, gender and fat mass. In conclusion, circulating omentin-1 may become a marker of metabolic dysfunction integrating insulin sensitivity, markers of adipose-tissue metabolism and BP as early as in prepubertal childhood.

Lower free thyroxin associates with a less favorable metabolic phenotype in healthy pregnant women.

CONTEXT: A lower free T(4) (fT4), within the euthyroid range, has been shown in adults to associate with an adverse metabolic phenotype. Thyroid physiology changes significantly during gestation and affects maternal and fetal well-being. OBJECTIVE: The aim of the study was to test the hypothesis that a lower serum fT4 in healthy euthyroid pregnant women is related to a less favorable metabolic phenotype and to fetal or placental weight. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: We examined associations of thyroid function tests (TSH and fT4) and the free T(3) (fT3)-to-fT4 ratio (as a proxy of deiodinase activity) with a metabolic profile [preload and postload glucose, glycosylated hemoglobin (HbA1c), high molecular-weight (HMW)-adiponectin, homeostasis model of assessment for insulin resistance (HOMA-IR), and serum lipids] in 321 healthy pregnant women. All women were euthyroid and had negative anti-thyroid peroxidase antibodies. None received thyroid hormone replacement. Blood tests were performed in women between 24 and 28 wk gestation. Placentas and newborns were weighed at birth. RESULTS: Circulating TSH did not relate to metabolic parameters, but decreasing fT4 and increasing fT3-to-fT4 ratio associated with a less favorable metabolic phenotype, as judged by higher postload glucose, HbA1c, fasting insulin, HOMA-IR, and triglycerides, and by a lower HMW-adiponectinemia (all P ≤ 0.005). In multiple regression analyses, fT4 was independently associated with HbA1c (ß = -0.135; P = 0.038), HMW-adiponectin (ß = 0.218; P < 0.001), and placental weight (ß = -0.185; P < 0.005), whereas the fT3-to-fT4 ratio was independently associated with maternal body mass index (ß = 0.265; P < 0.001), HMW-adiponectinemia (ß = -0.237; P < 0.002), HOMA-IR (ß = 0.194; P = 0.014), and placental weight (ß = 0.174; P = 0.020). CONCLUSION: In pregnant women without a history of thyroid dysfunction, lower concentrations of fT4 and a higher conversion of fT4 to fT3, as inferred by changes in the fT3-to-fT4 ratio, were found to be associated with a less favorable metabolic phenotype and with more placental growth.