Giorgia Sebastiani

The Association between the FTO Gene and Fat Mass in Humans Develops by the Postnatal Age of Two Weeks

OBJECTIVE Little is known about the genetic determinants of fat mass around birth. We hypothesized that the common rs9939609 single-nucleotide polymorphism (SNP) in FTO is associated with fat mass and metabolic parameters in neonates. DESIGN We conducted a cross-sectional, hospital-based study. PATIENTS Patients included 234 full-term, healthy newborns [122 girls and 112 boys; gestational age (mean, range), 39.0 (37.0-42.0) wk; birth weight, 3.2 (1.9-4.2) kg]. METHODS Cord-blood insulin, IGF-I, IGF-binding protein-1, adiponectin, and visfatin were measured by specific immunoassays. Body composition was assessed by dual-energy x-ray absorptiometry at about 13 d (range, 9-20 d). Genotyping of rs9939609 was achieved by restriction fragment length polymorphism analysis. RESULTS The rs9939609 SNP in FTO was not associated with birth weight; however, it was associated with serum visfatin (P < 0.001), with weight and ponderal index at age 2 wk (P < 0.05), and with total, truncal, and abdominal fat (P < 0.05 to P = 0.01), so that AA homozygotes had 37% higher plasma visfatin concentration and 17, 20, and 17% higher total, truncal, and abdominal fat mass, respectively, than T-carrier neonates. CONCLUSION Our findings support a role of the common rs9939609 SNP in FTO gene in the early stages of fat accretion in humans and disclose novel associations between this SNP and both serum visfatin and abdominal fat mass in neonates.

Gender specificity of body adiposity and circulating adiponectin, visfatin, insulin, and insulin growth factor-I at term birth: relation to prenatal growth

CONTEXT Fetal development is thought to be gender specific for adiposity and circulating insulin and IGF-I but not adipokinemia, as judged by serum visfatin and adiponectin at term birth. We studied the potential relationship between these gender specificities and fetal growth. SETTING The study was conducted at a university hospital. STUDY POPULATION Subjects included 96 strictly matched neonates born appropriate for gestational age (AGA; 24 girls, 24 boys) or small for gestational age (SGA; 24 girls, 24 boys). MAIN OUTCOMES Outcomes included serum insulin, IGF-I, visfatin, total and high-molecular-weight (HMW) adiponectin, osteocalcin at term birth, and neonatal body composition by absorptiometry. RESULTS Cord insulin and IGF-I levels were higher in girls than boys (P < or = 0.01), in both the AGA and SGA subpopulation. In AGA newborns, fat and lean mass were each gender specific (P < 0.0001), whereas visfatin and total and HMW adiponectin were not. Conversely, in SGA newborns, visfatin and HMW adiponectin were gender specific (higher levels in girls), whereas body adiposity was not. In SGA fetuses, the distribution of adiponectin isoforms was in both genders shifted toward HMW (P < 0.005 vs. AGA). Cord osteocalcin did not differ by either gender or birth weight. CONCLUSION At term birth, the gender specificity of adiposity and circulating visfatin and HMW adiponectin appeared to depend on prenatal growth, whereas the gender specificity of insulin and IGF-I levels did not. The fetal shift in adiponectin isoforms may contribute to explain why SGA newborns tend to be hypersensitive to insulin.

Body Composition and Circulating High-Molecular-Weight Adiponectin and IGF-I in Infants Born Small for Gestational Age: Breast- Versus Formula-Feeding

Prenatal growth restraint, if followed by postnatal overweight, confers risk for adult disease including diabetes. The mechanisms whereby neonatal nutrition may modulate such risk are poorly understood. We studied the effects of nutrition (breast-feeding [BRF] vs. formula-feeding [FOF]) on weight partitioning and endocrine state (as judged by high-molecular-weight [HMW] adiponectin and IGF-I) of infants born small for gestational age (SGA). Body composition (by absorptiometry), HMW adiponectin, and IGF-I were assessed at birth and 4 months in BRF infants born appropriate for gestational age (AGA; n = 72) and SGA infants receiving BRF (n = 46) or FOF (n = 56), the latter being randomized to receive a standard (FOF1) or protein-rich formula (FOF2). Compared with AGA-BRF infants, the catchup growth of SGA infants was confined to lean mass, independently of nutrition. Compared with AGA-BRF infants, SGA-BRF infants had normal HMW adiponectin and IGF-I levels at 4 months, whereas SGA-FOF infants had elevated levels of HMW adiponectin (particularly SGA-FOF1) and IGF-I (particularly SGA-FOF2). In conclusion, neonatal nutrition seems to influence endocrinology more readily than body composition of SGA infants. Follow-up will disclose whether the endocrine abnormalities in SGA-FOF infants can serve as early markers of an unfavorable metabolic course and whether they may contribute to design early interventions that prevent subsequent disease, including diabetes.

Oral Contraception vs Insulin Sensitization for 18 Months in Nonobese Adolescents With Androgen Excess: Posttreatment Differences in C-Reactive Protein, Intima-Media Thickness, Visceral Adiposity, Insulin Sensitivity, and Menstrual Regularity

BACKGROUND An oral estro-progestagen is the standard medication given to adolescent girls with androgen excess, even when those girls are not at risk of pregnancy. AIM The aim of this study was to compare on-treatment and post-treatment effects of intervention with an oral contraceptive vs an insulin-sensitizing treatment for androgen excess in nonobese adolescents. DESIGN This was a randomized, open-label trial. STUDY POPULATION Subjects were nonobese adolescent girls with hyperinsulinemic androgen excess and without risk of pregnancy (mean age, 16 years; body mass index, 23 kg/m²; n = 34). INTERVENTIONS The effects of treatment with ethinylestradiol-cyproteroneacetate (EE-CA) vs a low-dose combination of pioglitazone (7.5 mg/d), flutamide (62.5 mg/d), and metformin (850 mg/d) (PioFluMet) for 18 months were studied. Posttreatment follow-up was for 6 months. MAIN OUTCOME MEASURES Androgen excess (hirsutism and acne scores and serum testosterone), glucose-stimulated insulinemia, circulating C-reactive protein, carotid intima media thickness, body composition (absorptiometry), abdominal fat partitioning (magnetic resonance imaging), and menstrual regularity were measured. RESULTS EE-CA and PioFluMet attenuated androgen excess similarly but had divergent, and even opposing, effects on other outcomes. Six months posttreatment, the PioFluMet-treated girls had a lower glucose-induced insulinemia, a lower C-reactive protein level, and a thinner intima media than the EE-CA-treated girls, and they were viscerally less adipose, had a higher lean mass, and were more likely to have regular cycles. CONCLUSIONS The on-treatment and post-treatment effects of PioFluMet compared favorably with those of oral contraception in nonobese adolescents with androgen excess. The intervention whereby androgen excess is reduced in adolescence influences the post-treatment phenotype. PioFluMet-like interventions in adolescence may thus hold the potential to prevent part of the androgen-excess phenotype in adulthood, including adiposity and subfertility.

Treatment of androgen excess in adolescent girls: ethinylestradiol-cyproteroneacetate versus low-dose pioglitazone-flutamide-metformin.

OBJECTIVE The aim was to perform a first comparison between the effects of a classic therapy and those of a novel treatment for androgen excess in adolescent girls. DESIGN AND SETTING We conducted a randomized, open-labeled trial at a university hospital. PARTICIPANTS Thirty-four adolescents with hyperinsulinemic androgen excess and without risk of pregnancy participated in the study. INTERVENTIONS Ethinyl estradiol-cyproterone acetate (EE-CA) vs. a low-dose combination of pioglitazone, flutamide, and metformin (PioFluMet) was administered for 6 months. MAIN OUTCOME MEASURES We assessed hirsutism and acne scores; androgen excess; fasting insulin, lipid profile, C-reactive protein, high molecular-weight adiponectin, leptin, follistatin; carotid intima-media thickness; body composition (absorptiometry); and abdominal fat partitioning (magnetic resonance imaging). RESULTS EE-CA and PioFluMet attenuated the androgen excess comparably but had divergent effects on fasting insulinemia; on circulating cholesterol, triglycerides, C-reactive protein, high molecular-weight adiponectin, leptin, and follistatin; on carotid intima-media thickness; on lean mass; and on abdominal, visceral, and hepatic fat, with all these divergences pointing to a healthier condition on low-dose PioFluMet. CONCLUSION Low-dose PioFluMet compared favorably to EE-CA in adolescents with androgen excess and without pregnancy risk. The efficacy and safety of low-dose PioFluMet remain to be studied over a longer term and in larger cohorts.

Breast-feeding vs Formula-feeding for Infants Born Small-for-Gestational-Age: Divergent Effects on Fat Mass and on Circulating IGF-I and High-Molecular-Weight Adiponectin in Late Infancy

CONTEXT Fetal growth restraint, if followed by rapid weight gain, confers risk for adult disease including diabetes. How breast-feeding may lower such risk is poorly understood. OBJECTIVE, STUDY PARTICIPANTS, INTERVENTION, OUTCOMES: In infants born small-for-gestational-age (SGA), we studied the effects of nutrition in early infancy (breast-feeding vs formula-feeding; BRF vs FOF) on weight partitioning and endocrine markers in late infancy. Body composition (by absorptiometry), fasting glycemia, insulin, IGF-I, and high-molecular-weight (HMW) adiponectin were assessed at 4 and 12 months in BRF controls born appropriate-for-GA (N = 31) and in SGA infants receiving BRF (N = 48) or FOF (N = 51), the latter being randomized to receive a standard formula (FOF1) or a protein-rich formula (FOF2). SETTING The study was conducted in a University Hospital. RESULTS SGA-BRF infants maintained a low fat mass and normal levels of IGF-I and HMW adiponectin. In contrast, SGA-FOF infants normalized their body composition by gaining more fat; this normalization was accompanied by a marked fall in HMW adiponectinemia and, in FOF2 infants, by elevated IGF-I levels. In late infancy, SGA-BRF infants were most sensitive to insulin, even more sensitive than appropriate-for-GA-BRF controls. CONCLUSIONS Because the health perspectives are better for SGA-BRF than for SGA-FOF infants, the present results suggest that FOF for SGA infants should aim at maintaining normal IGF-I and HMW-adiponectin levels rather than at normalizing body composition. Nutriceutical research for SGA infants may thus have to be redirected.

Abundance of Circulating Preadipocyte Factor 1 in Early Life

OBJECTIVE Soluble preadipocyte factor 1 (Pref-1) inhibits adipocyte differentiation. We tested whether circulating levels of soluble Pref-1 are higher in smaller fetuses. RESEARCH DESIGN AND METHODS We performed longitudinal assessments of circulating Pref-1 in infants born appropriate for gestational age (AGA) or small for gestational age (SGA) and also in late-gestational women and in newborns on days 2 and 3. RESULTS At birth, Pref-1 levels were ~100-fold higher than in adults, being in SGA fetuses ~50% higher than in AGA fetuses. By age 4 months, Pref-1 had reached near-adult levels and the original AGA versus SGA difference had disappeared. Pref-1 levels were low in late-gestational women and were still elevated in newborns. CONCLUSIONS Pref-1 is abundantly present in the fetus, is higher in SGA than in AGA fetuses, and is likely to be of fetal origin. We speculate that Pref-1 in early life contributes to variation in postnatal adipocyte numbers, in the subsequent expandability of adipose tissue, and thus in the susceptibility to diabetes in later life.

Low Body Adiposity and High Leptinemia in Breast-fed Infants Born Small-for-Gestational-Age

Breast-fed infants born small-for-gestational-age (SGA) (n = 28) were found to develop lower adiposity across early infancy, when compared with appropriate-for-gestational age infants (n = 46). The SGA infants were also found to have 2-fold higher (P < .001) levels of circulating leptin at 4 months. This paradoxical hyperleptinemia in early infancy may contribute to a program that produces a process from fetal underweight to adult overweight.

High-Molecular-Weight Adiponectin in Children Born Small- or Appropriate-for-Gestational-Age

Longitudinal data collected from children ages 2 until 6 years, who were born appropriate-for-gestational-age or small-for-gestational-age, indicate that the latter have a normal body fat fraction and normal high-molecular-weight adiponectinemia at age 2 years and that they accumulate excess adipose tissue and have low adiponectin levels by age 4 to 6 years.

Placental and Cord Blood Methylation of Genes Involved in Energy Homeostasis: Association with Fetal Growth and Neonatal Body Composition

Low weight at birth is associated with subsequent susceptibility to diabetes. Epigenetic modulation is among the mechanisms potentially mediating this association. We performed a genome-wide DNA methylation analysis in placentas from term infants born appropriate-for-gestational-age (AGA) or small-for-gestational-age (SGA) to identify new genes related to fetal growth and neonatal body composition. Candidate genes were validated by bisulfite pyrosequencing (30 AGA, 21 SGA) and also analyzed in cord blood. Gene expression analyses were performed by RT-PCR. Neonatal body composition was assessed by dual X-ray absorptiometry at age 2 weeks. The ATG2B, NKX6.1, and SLC13A5 genes (respectively related to autophagy, β-cell development and function, and lipid metabolism) were hypermethylated in placenta and cord blood from SGA newborns, whereas GPR120 (related to free fatty acid regulation) was hypomethylated in placenta and hypermethylated in cord blood. Gene expression levels were opposite to methylation status, and both correlated with birth weight, circulating IGF-I, and total and abdominal fat at age 2 weeks. In conclusion, alterations in methylation and expression of genes involved in the regulation of energy homeostasis were found to relate to fetal growth and neonatal body composition and thus may be among the early mechanisms modulating later susceptibility to diabetes.