Impact of Early Infant Growth, Duration of Breastfeeding and Maternal Factors on Total Body Fat Mass and Visceral Fat at 3 and 6 Months of Age.

BACKGROUND: Accelerated gain in fat mass in the first months of life is considered to be a risk factor for adult diseases, given the tracking of infancy fat mass into adulthood. Our objective was to assess the influence of early growth, type of feeding and maternal variables on fat mass in early life. METHODS: In 300 healthy term infants, we longitudinally measured fat mass percentage (FM%) by air-displacement-plethysmography at 1, 3, and 6 months and abdominal visceral and subcutaneous fat measured by ultrasound at 3 and 6 months. RESULTS: Both gain in FM% and weight-for-length in the first 3 months were positively associated with FM% at 6 months of age and visceral fat at 3 months of age. Gain in FM% and weight-for-length between 3 and 6 months were both positively associated with visceral fat at 6 months. Breastfeeding duration associated positively with subcutaneous fat but not with visceral fat at 3 and 6 months. Maternal characteristics did not associate with FM% or visceral fat at 3 or 6 months. CONCLUSION: Higher gain in FM% or in weight-for-length in the first postnatal months leads not only to higher FM% but also more to accumulation of visceral fat. Exclusive breastfeeding appears to promote subcutaneous but not visceral fat in the first 6 months.

Association Between Fat Mass in Early Life and Later Fat Mass Trajectories.

Importance: A rapid increase in weight in early life is associated with an increased risk for adiposity and cardiovascular diseases at age 21 years and beyond. However, data on associations of early change in measured fat mass percentage (FM%) with adiposity development are lacking. Objective: To investigate whether a rapid increase in FM% in the first months of life is associated with higher trajectories of body fat mass during the first 2 years of life. Design, Setting, and Participants: A birth cohort consisting of 401 healthy, term-born infants of the Sophia Pluto Cohort Study was analyzed. Participants were born between January 7, 2013, and October 13, 2017. Data were analyzed from February 1, 2020, to May 20, 2020. Interventions: Longitudinal measurements of FM% by air-displacement plethysmography and dual-energy x-ray absorptiometry, and abdominal subcutaneous and visceral fat mass (FM) by ultrasonography in infants at ages 1, 3, 6, 9, 12, 18, and 24 months. A rapid increase in FM% was defined as a change in FM% of greater than 0.67 standard deviation scores (SDS). Main Outcomes and Measures: Associations between change in FM% SDS in the first and second 6-month period of life with body composition at age 2 years and whether a rapid increase in FM% SDS during the first 6 months leads to higher body FM and abdominal FM trajectories during the first 2 years of life. Results: Of the 401 participants, 228 infants (57%) were male. Change in FM% SDS from age 1 to 6 months was positively associated with FM% (ß, 0.044; 95% CI, 0.017-0.068), FMI (ß, 0.061; 95% CI, 0.032-0.091), and abdominal subcutaneous FM (ß, 0.064; 95% CI, 0.036-0.092) at age 2 years, but not with visceral FM. In contrast, no associations were found within the 6- to 12-month period. Infants with a rapid increase in FM% of greater than 0.67 SDS in the first 6 months of life had higher trajectories of FM%, FM index, and subcutaneous FM during the first 2 years of life (all P≤.001), but visceral FM index was not significantly different compared with infants without a rapid increase (P = .12). Conclusions and Relevance: In this study, only the change in FM% in the first 6 months of life was associated with more adiposity at age 2 years. Infants with a rapid increase in FM% had higher trajectories of FM% and FM index during the first 2 years of life. These findings appear to support a critical window for adiposity programming in early life.

Longitudinal body composition assessment in healthy term-born infants until 2 years of age using ADP and DXA with vacuum cushion.

OBJECTIVES: Accelerated gain in fat mass (FM) in early life increases the risk for adult diseases. Longitudinal data on infant body composition are crucial for clinical and research use, but very difficult to obtain due to limited measurement tools and unsuccessful measurements between age 6-24 months. We compared FM% by dual-energy X-ray absorptiometry (DXA), with cushion to reduce movement artifacts, with FM% by air-displacement plethysmography (ADP) and evaluated the reliability of this cushion during DXA by comparing FM% with and without cushion. Subsequently, we constructed sex-specific longitudinal body composition charts from 1-24 months. METHODS: In 692 healthy, term-born infants (Sophia Pluto Cohort), FM% was measured by ADP from 1-6 months and DXA with cushion from 6-24 months. At 6 months, FM% was measured in triplicate by ADP and DXA with and without cushion(n = 278), later on in smaller numbers. RESULTS: At 6 months, mean FM% by DXA with cushion was 24.1 and by ADP 25.0, mean difference of 0.9% (Bland-Altman p = 0.321, no proportional bias). Mean FM% by DXA without cushion was 12.5% higher compared to ADP (Bland-Altman p < 0.001). DXA without cushion showed higher mean FM% compared to DXA with cushion (+11.6%, p < 0.001) at 6 months. Longitudinally, FM% increased between 1-6 months and decreased from 6-24 months(both p < 0.001). CONCLUSIONS: In infants, DXA scan with cushion limits movement artifacts and shows reliable FM%, comparable to ADP. This allowed us to construct longitudinal body composition charts until 24 months. Our study shows that FM% increases from 1-6 months and gradually declines until 24 months.

P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development.

In multiple endocrine neoplasia syndrome Type 2 (MEN2), medullary thyroid carcinoma (MTC) and pheochromocytoma (PC) are associated with hereditary activating germ-line mutations in the RET proto-oncogene. Also in a large percentage of sporadic MTCs and PCs, somatic RET mutations appear to be involved in tumor formation. In one single MEN2 family an extensive variety in disease expression may be observed, indicating that additional genetic events are responsible for progression of the disease towards a more aggressive phenotype. However, these additional mutations in both hereditary and sporadic MTC and PC development are largely unknown. Here, we show for the first time the presence of somatic mutations in the cell cycle regulator P18 in human RET-associated MTCs and PCs. Each of these mutations causes an amino acid substitution in the cyclin dependent kinase-interacting region of P18(INK4C). Since these mutations partly inhibited P18(INK4C) function and reduced its stability, our findings implicate P18 as a tumor suppressor gene involved in human MTC and PC development.

An infant formula with large, milk phospholipid-coated lipid droplets containing a mixture of dairy and vegetable lipids supports adequate growth and is well tolerated in healthy, term infants.

BACKGROUND: Lipid droplets in human milk have a mode diameter of ∼4 µm and are surrounded by a native phospholipid-rich membrane. Current infant milk formulas (IMFs) contain small lipid droplets (mode diameter ∼0.5 µm) primarily coated by proteins. A concept IMF was developed mimicking more closely the structure and composition of human milk lipid droplets. OBJECTIVES: This randomized, controlled, double-blind equivalence trial evaluates the safety and tolerance of a concept IMF with large, milk phospholipid-coated lipid droplets (mode diameter 3-5 µm) containing vegetable and dairy lipids in healthy, term infants. METHODS: Fully formula-fed infants were enrolled up to 35 d of age and randomly assigned to 1 of 2 formulas until 17 wk of age: 1) Control IMF with small lipid droplets containing vegetable oils (n = 108); or 2) Concept IMF with large, milk phospholipid-coated lipid droplets comprised of 48% dairy lipids (n = 115). A group of 88 breastfed infants served as reference. Primary outcome was daily weight gain during intervention. Additionally, number and type of adverse events, growth, and tolerance parameters were monitored. RESULTS: Equivalence of daily weight gain was demonstrated (Concept compared with Control IMF: -1.37 g/d; 90% CI: -2.71, -0.02; equivalence margin ± 3 g/d). No relevant group differences were observed in growth, tolerance and number, severity, or relatedness of adverse events. We did observe a higher prevalence of watery stools in the Concept than in the Control IMF group between 5 and 12 wk of age (P < 0.001), closer to the stool characteristics observed in the breastfed group. CONCLUSIONS: An infant formula with large, milk phospholipid-coated lipid droplets containing dairy lipids is safe, well tolerated, and supports an adequate growth in healthy infants. This trial was registered in the Dutch Trial Register (www.trialregister.nl) as NTR3683.

Longitudinal fat mass and visceral fat during the first 6 months after birth in healthy infants: support for a critical window for adiposity in early life.

INTRODUCTION: Body composition in early life influences the development of obesity during childhood and beyond. It is, therefore, important to adequately determine longitudinal body composition during the first months of life. PATIENTS AND METHODS: In 203 healthy term infants, we investigated longitudinal body composition, including fat mass percentage (FM%) and fat-free mass (FFM), by air-displacement plethysmography, at 1, 3 and 6 months of age and abdominal visceral fat and abdominal subcutaneous fat, by ultrasound, at 3 and 6 months. RESULTS: We found a significant increase in FM% between 1 and 3 months but not between 3 and 6 months (p < 0.001, p = 0.098, respectively). Girls had higher FM% than boys at 1 and 6 months (p = 0.05, p < 0.001 respectively) and less FFM than boys at 1, 3 and 6 months (p = 0.02, p = 0.02, p < 0.001, respectively). There was a large variation in FM% at all ages even between infants with similar weight standard deviation scores. Visceral fat and abdominal subcutaneous fat did not change between 3 and 6 months. FM% was highly correlated with abdominal subcutaneous fat but not with visceral fat. CONCLUSION: Changes in FM% occur mainly in the first 3 months of life, and FM%, visceral and abdominal subcutaneous fat do not change between 3 and 6 months, supporting the concept of a critical window for adiposity development in the first three months of life. In addition, our study provides longitudinal reference data of FM%, FFM, visceral fat and abdominal subcutaneous fat during the first 6 months of life.

Differences in the anthropometry of Asian children and its role in metabolic health in later life: A narrative review.

BACKGROUND: The increasing incidence of childhood obesity in Asia could be a reflection of early life programming in which environmental/nutritional challenges during pregnancy and first two years of life (the so-called first 1000 days) influence later health. OBJECTIVE OF NARRATIVE REVIEW: To assess differences/similarities of anthropometric measures in early life and their influences on metabolic health risk in later life among children in Asia. METHODS: Literature search for publication in English using selected key words from Medline (PubMed), Scopus, Science Direct and Google Scholar published from 1994 to October 2014. Some comparisons with Caucasian setting were made when relevant. RESULTS: From 152 publications selected for this narrative review, differences in foetal growth and birth weight were deducted between Asian and Caucasian children. Infants in India and Hong Kong had increased fat mass at birth and early infancy as compared to those from other parts of the world. Pre- and during pregnancy conditions influenced birth weight; feeding practices and gender influenced post-natal growth and body composition development. High and low birth weights followed by rapid postnatal growth were linked to increased risks of obesity, insulin resistance and high blood pressure in later life. CONCLUSION: Foetal and postnatal growth trajectories are different between countries within and outside Asia. Extremes in birth weight followed by rapid postnatal growth were linked to increased risks of metabolic health of children in this region. As there is limited evidence in Asia, it is important to conduct thorough investigations by using longitudinal studies on early life programming.

A novel infant milk formula concept: Mimicking the human milk fat globule structure.

Human milk (HM) provides all nutrients to support an optimal growth and development of the neonate. The composition and structure of HM lipids, the most important energy provider, have an impact on the digestion, uptake and metabolism of lipids. In HM, the lipids are present in the form of dispersed fat globules: large fat droplets enveloped by a phospholipid membrane. Currently, infant milk formula (Control IMF) contains small fat droplets primarily coated by proteins. Recently, a novel IMF concept (Concept IMF) was developed with a different lipid architecture, Nuturis(®), comprising large fat droplets with a phospholipid coating. Confocal laser scanning microscopy (CLSM), with appropriate fluorescent probes, and transmission electron microscopy were used to determine and compare the interfacial composition and structure of HM fat globules, Concept IMF fat droplets and Control IMF fat droplets. The presence of a trilayer-structured HM fat globule membrane, composed of phospholipids, proteins, glycoproteins and cholesterol, was confirmed; in addition exosome-like vesicles are observed within cytoplasmic crescents. The Control IMF fat droplets had a thick protein-only interface. The Concept IMF fat droplets showed a very thin interface composed of a mixture of phospholipids, proteins and cholesterol. Furthermore, the Concept IMF contained fragments of milk fat globule membrane, which has been suggested to have potential biological functions in infants. By mimicking more closely the structure and composition of HM fat globules, this novel IMF concept with Nuturis(®) may have metabolic and digestive properties that are more similar to HM compared to Control IMF.

Induction of Staphylococcus aureus-specific IgA and agglutination potency in milk of cows by mucosal immunization.

Lactating cows were immunized with inactivated Staphylococcus aureus strains and concentrated culture supernatants. Application of a repeated mucosal immunization scheme resulted in significant levels of S. aureus-specific IgA in milk of dairy cows. Average IgA titers against whole cell S. aureus increased during the first 10 weeks of immunization after which a plateau level was reached and maintained during lactation. Immune whey agglutinated both bovine and human S. aureus strains including methicillin-resistant S. aureus (MRSA) strains and recognized extracted S. aureus proteins on Western blot. ELISAs to quantify milk IgA reactive with a number of S. aureus virulence proteins (e.g. enterotoxins, microbial surface component recognizing adhesive matrix molecules (MSCRAMMs) and immune modulating proteins) and cell wall components, demonstrated the polyclonality of the IgA. Correlations observed between agglutination and specific IgA titers for whey and for purified IgA suggested functionality of the induced antibodies. Milk from immunized cows may provide a way of producing potentially therapeutic polyclonal antibodies against S. aureus colonization and infection.

Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development.

Activating mutations in the RET proto-oncogene are associated with both familial and sporadic medullary thyroid carcinoma (MTC) development; however, the genetic mechanisms underlying MTC tumorigenesis remain largely unknown. Recently, we have identified somatic inactivating mutations in the cell cycle inhibitor gene P18 in human MTC, which coincided with activating RET mutations, suggesting a role for loss of P18 in combination with oncogenic RET in the multistep process of MTC development. Therefore, we crossed transgenic mice expressing oncogenic RET (RET2B) with mice lacking p18 (and p27, another cell cycle inhibitor) and monitored MTC development. RET2B;p18(+/-) mice and RET2B;p18(-/-) mice developed MTC with a highly increased incidence compared with their corresponding single mutant littermates. In addition, expression of oncogenic RET causes an earlier age of onset and larger MTCs in p18(-/-);p27(+/-) mice. In a subset of MTCs of RET2B;p18(+/-)(;p27(+/-)) mice, p18(Ink4c) expression was completely lost. This loss of p18(Ink4c) expression correlated with higher proliferation rates as well as with larger MTCs, indicating that loss of p18 in combination with oncogenic RET not only increases the risk for MTC development but also enhances MTC progression. Our data strongly indicate that oncogenic RET and loss of p18 cooperate in the multistep tumorigenesis of MTC.

A novel RET kinase-beta-catenin signaling pathway contributes to tumorigenesis in thyroid carcinoma.

The RET receptor tyrosine kinase has essential roles in cell survival, differentiation, and proliferation. Oncogenic activation of RET causes the cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) and is a frequent event in sporadic thyroid carcinomas. However, the molecular mechanisms underlying RET's potent transforming and mitogenic signals are still not clear. Here, we show that nuclear localization of beta-catenin is frequent in both thyroid tumors and their metastases from MEN 2 patients, suggesting a novel mechanism of RET-mediated function through the beta-catenin signaling pathway. We show that RET binds to, and tyrosine phosphorylates, beta-catenin and show that the interaction between RET and beta-catenin can be direct and independent of cytoplasmic kinases, such as SRC. As a result of RET-mediated tyrosine phosphorylation, beta-catenin escapes cytosolic down-regulation by the adenomatous polyposis coli/Axin/glycogen synthase kinase-3 complex and accumulates in the nucleus, where it can stimulate beta-catenin-specific transcriptional programs in a RET-dependent fashion. We show that down-regulation of beta-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. Together, our data show that a beta-catenin-RET kinase pathway is a critical contributor to the development and metastasis of human thyroid carcinoma.