Janna A. van Diepen

Importance: Childhood obesity increases cardiometabolic risk during childhood among individuals aged 2-18 years. These cardiometabolic outcomes include glucose intolerance, dyslipidemia, hypertension, metabolic syndrome, and type 2 diabetes (T2D). In the current state of research, a comprehensive review identifying all early-life exposures and risk factors that could predict cardiometabolic risk in children is lacking. Objective: To identify and evaluate the predictive early-life risk factors during the first 1,000 days of life, including preconception, pregnancy and birth, and early infancy periods for cardiometabolic risk outcomes in childhood. Evidence review: The present systematic review of existing literature was conducted to revise and search selected electronic databases (Medline, EMBASE, WEB OF SCIENCE, SCOPUS, and Cochrane CENTRAL) for longitudinal studies published between the database’s inception and August ¹⁷ , 2022. This systematic review protocol was registered to PROSPERO, CRD42022355152, and following the PRISMA guidelines. We selected articles that studied the risk factors in mothers, fathers and infants, from preconception to infancy, for childhood cardiometabolic outcomes between 2 and 18 years. Findings: In 68 studies, we identified 229 associations between exposures and childhood cardiometabolic outcomes namely glucose intolerance, dyslipidemia, hypertension, metabolic syndrome, and T2D. The majority of associations (n=162) were positively associated with cardiometabolic risk factors. Pregnancy and birth risk factors were the categories with the most reported associations (86%). Among them, the most frequently assessed characteristics were birth anthropometrics (n=75), sociodemographics data (n=47), and pregnancy complications factors (n=34). However, we only identified few risk factors during preconception. In infancy period, breastfeeding (n=16) and infant anthropometrics (n=15) were consistently associated with cardiometabolic outcomes. In all periods, the most studied associations were identified for hypertension and metabolic syndrome. Conclusions and relevance: Birth anthropometrics, sociodemographics, and pregnancy complication factors were the most frequently reported predictive factors associated with a higher risk for cardiometabolic outcomes in children, particularly hypertension and metabolic syndrome. These results of this study are useful for predicting the risk for childhood cardiometabolic outcomes and for the modifiable factors. They also may facilitate the design of approaches aimed at the alteration of several behaviours from birth to infancy, encompassing both the maternal and paternal influences, as well as the preconception to infancy transition period. Future studies evaluating early-life risk factors with scarce scientific evidence, such as paternal and preconception factors, are urgently needed. Key points: Question: What is the existing evidence of early-life risk factors during the first 1000 days of life that are associated with cardiometabolic dysfunction between 2 and 18 years? Findings: Birth anthropometrics, pregnancy complications, sociodemographics and lifestyle factors are the most frequently reported associated exposures with hypertension and metabolic syndrome in children. Meaning: Identifying early-life risk factors and changing behavior patterns throughout preconception and infancy can contribute to prevent metabolic diseases later in childhood.

Increased insulin levels may support the development of neural circuits involved in cognition, while chronic mild inflammation may also result in cognitive impairment. This study aimed to gain more insight into whether cognition is already impacted during adolescence in a genetic rat model for obesity and type 2 diabetes. Visual discrimination learning throughout adolescence and the level of motivation during early adulthood were investigated in Zucker Diabetic Fatty (ZDF) obese and ZDF lean rats using operant touchscreens. Blood glucose, insulin, and lipids were longitudinally analyzed. Histological analyses were performed in the liver, white adipose tissues, and the prefrontal cortex. Prior to the experiments with the genetic ZDF research model, all experimental assays were performed in two groups of outbred Long Evans rats to investigate the effect of different feeding circumstances. Adolescent ZDF obese rats outperformed ZDF lean rats on visual discrimination performance. During the longitudinal cognitive testing period, insulin levels sharply increased over weeks in ZDF obese rats and were significantly enhanced from 6 weeks of age onwards. Early signs of liver steatosis and enlarged adipocytes in white adipose tissue were observed in early adult ZDF obese rats. Histological analyses in early adulthood showed no group differences in the number of prefrontal cortex neurons and microglia, nor PSD95 and SIRT1 mRNA expression levels. Together, our data show that adolescent ZDF obese rats even display enhanced cognition despite their early diabetic profile.

Increased insulin levels may support the development of neural circuits involved in cognition, while chronic mild inflammation may also result in cognitive impairment. This study aimed to gain more insight into whether cognition is impacted already during adolescence in a genetic rat model for obesity and type 2 diabetes. Cognitive functioning throughout adolescence and early adulthood was investigated in Zucker Diabetic Fatty (ZDF), ZDF lean and healthy outbred Long Evans rats using operant touchscreens. Blood glucose, insulin and lipids were longitudinally analyzed. Histological analyses were performed in the liver, white adipose tissues and the prefrontal cortex. Adolescent ZDF obese rats outperformed lean rats on visual discrimination performance. During the longitudinal cognitive testing period, insulin levels sharply increased over weeks in ZDF obese rats and were significantly enhanced from 6 weeks of age onwards. Early signs of liver steatosis and enlarged adipocytes in white adipose tissue were observed in ZDF early adult obese rats. Histological analyses at early adulthood showed no group differences in the number of prefrontal cortex neurons and microglia, nor PSD95 and SIRT1 mRNA expression levels. Together, our data show that adolescent obese ZDF rats even display enhanced cognition despite their early diabetic profile.

Background: Infant gut microbiota composition is influenced by various factors early in life. Here, we investigate associations between infant gut microbiome development, infant age, breastfeeding duration, and human milk oligosaccharides (HMO) composition in breastmilk.Methods: A total of 94 mother-infant pairs were recruited as part of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) (Cambridge, UK). Infant stool samples (n= 337) were collected at 2 week, 6 week, 3 month, and 6 month of age. The 16S rRNA V3-V4 rRNA region was sequenced using MiSeq Illumina to determine microbiota composition and diversity. Mother’s hindmilk samples were collected at birth, 2 week, 6 week, 3 month, and 6 month postpartum. Concentrations of five neutral [2′FL, 3′FL, lacto-N-fucopentaose 1 (LNFP1), LNnT, LNT] and two acidic (3′SL, and 6′SL) HMOs were measured in all milk samples using High-Performance Anion-Exchange Chromatography with Pulsed Amperometric Detection (HPAEC-PAD). We explored the associations between infant gut microbiome parameters and age, duration of exclusive breastfeeding (EBF), and levels of individual HMOs.Results: Bifidobacteriumwas the most abundant genus in infant stool at all-time points, irrespective of breastfeeding duration, with an overall mean relative abundance of 70%. The relative abundance ofB. bifidumin stool from infants who were breastfed for longer than 6 months was significantly higher compared to the infant breastfed up to 3 months (p= 0.0285). Alpha-diversity (both Shannon and ASV-level Richness) of infant gut microbiota showed a biphasic change with infant age, decreasing from 2 weeks until 3 months and then increasing until 6 months of age.Bifidobacteriumrelative abundance was associated with higher concentrations of 2′FL and LNFP1 in breastmilk across all time-points (p= 0.049 and 0.017, respectively), with trends toward a higher abundance ofB. longumspecies. No significant association withBifidobacteriumwas found for breastmilk LNnT, 3′SL, and 6′SL levels.Conclusion: Our study is in line with previous data demonstrating that EBF duration in the first months of life impacts infant gut microbiota composition. The observed links between specific HMOs in breastmilk and bacteria in infant stool provide evidence of how mother’s milk affects infant microbiome development.

Butyrate in human milk (HM) has been suggested to reduce excessive weight and adipo-sity gains during infancy. However, HM butyrate’s origins, determinants, and its influencing mechanism on weight gain are not completely understood. These were studied in the prospective longitudinal Cambridge Baby Growth and Breastfeeding Study (CBGS-BF), in which infants (n = 59) were exclusively breastfed for at least 6 weeks. Infant growth (birth, 2 weeks, 6 weeks, 3 months, 6 months, and 12 months) and HM butyrate concentrations (2 weeks, 6 weeks, 3 months, and 6 months) were measured. At age 6 weeks, HM intake volume was measured by deuterium-labelled water technique and HM microbiota by 16S sequencing. Cross-sectionally at 6 weeks, HM butyrate was associated with HM microbiota composition (p = 0.036) although no association with the abundance of typical butyrate producers was detected. In longitudinal analyses across all time points, HM butyrate concentrations were overall negatively associated with infant weight and adiposity, and associations were stronger at younger infant ages. HM butyrate concentration was also inversely correlated with HM intake volume, supporting a possible mechanism whereby butyrate might reduce infant growth via appetite regulation and modulation of HM intake.

Growth patterns of breastfed infants show substantial inter-individual differences, partly influenced by breast milk (BM) nutritional composition. However, BM nutritional composition does not accurately indicate BM nutrient intakes. This study aimed to examine the associations between both BM intake volumes and macronutrient intakes with infant growth. Mother–infant dyads (n 94) were recruited into the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) from a single maternity hospital at birth; all infants received exclusive breast-feeding (EBF) for at least 6 weeks. Infant weight, length and skinfolds thicknesses (adiposity) were repeatedly measured from birth to 12 months. Post-feed BM samples were collected at 6 weeks to measure TAG (fat), lactose (carbohydrate) (both by ¹H-NMR) and protein concentrations (Dumas method). BM intake volume was estimated from seventy infants between 4 and 6 weeks using dose-to-the-mother deuterium oxide (²H₂O) turnover. In the full cohort and among sixty infants who received EBF for 3+ months, higher BM intake at 6 weeks was associated with initial faster growth between 0 and 6 weeks (β + se 3·58 + 0·47 for weight and 4·53 + 0·6 for adiposity gains, both P < 0·0001) but subsequent slower growth between 3 and 12 months (β + se − 2·27 + 0·7 for weight and −2·65 + 0·69 for adiposity gains, both P < 0·005). BM carbohydrate and protein intakes at 4–6 weeks were positively associated with early (0–6 weeks) but tended to be negatively related with later (3–12 months) adiposity gains, while BM fat intake showed no association, suggesting that carbohydrate and protein intakes may have more functional relevance to later infant growth and adiposity.

Scope: Milk fat globule membrane (MFGM) is an essential component of milk. Bovine MFGM (bMFGM) has been shown to support cognitive development and increase relative concentrations of serum phospholipids. This study investigates bioavailability of bMFGM components after oral administration in two preclinical models to explore whether dietary bMFGM induces parallel changes to plasma and brain lipidomes.Methods and results: Transgenic APOE*3.Leiden mice (n = 18 per group) and Sprague–Dawley rats (n = 12 per group) are fed bMFGM‐enriched (MFGM+) or Control diet, followed by phospholipid profile‐determination in plasma, hippocampus, and prefrontal cortex tissue by targeted mass spectrometry. Multivariate analysis of lipidomic profiles demonstrates a separation between MFGM+ and Control plasma across rodents. In plasma, sphingomyelins contributed the most to the separation of lipid patterns among both models, where three sphingomyelins (d18:1/14:0, d18:1/23:0, d18:1/23:1[9Z]) are consistently higher in the circulation of MFGM+ groups. A similar trend is observed in rat prefrontal cortex, although no significant separation of the brain lipidome is demonstrated.Conclusion: bMFGM‐enriched diet alters plasma phospholipid composition in rodents, predominantly increasing sphingomyelin levels in the systemic circulation with similar, but non‐significant, trends in central brain regions. These changes may contribute to the beneficial effects of bMFGM on neurodevelopment during early life.

Various lifestyle factors, including diet, physical activity, and sleep, have been studied in the context of children’s health. However, how these lifestyle factors contribute to the development of cognitive abilities, including spatial cognition, remains vastly understudied. One landmark in spatial cognitive development occurs between 2.5 and 3 years of age. For spatial orientation at that age, children learn to use allocentric reference frames (using spatial relations between objects as the primary reference frame) in addition to, the already acquired, egocentric reference frames (using one’s own body as the primary reference frame). In the current virtual reality study in a sample of 30–36-month-old toddlers (N = 57), we first demonstrated a marginally significant developmental shift in spatial orientation. Specifically, task performance with allocentric performance increased relative to egocentric performance (η_p² = 0.06). Next, we explored a variety of lifestyle factors, including diet, in relation to task performance, to explain individual differences. Screen time and gestational weight gain of the mother were negatively associated with spatial task performance. The findings presented here can be used to guide future confirmatory studies about the role of lifestyle factors in the development of spatial cognition.

Growth and nutrition during early life have been strongly linked to future health and metabolic risks. The Cambridge Baby Growth Study (CBGS), a longitudinal birth cohort of 2229 mother–infant pairs, was set up in 2001 to investigate early life determinant factors of infant growth and body composition in the UK setting. To carry out extensive profiling of breastmilk intakes and composition in relation to infancy growth, the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) was established upon the original CBGS. The strict inclusion criteria were applied, focusing on a normal birth weight vaginally delivered infant cohort born of healthy and non-obese mothers. Crucially, only infants who were exclusively breastfed for the first 6 weeks of life were retained in the analysed study sample. At each visit from birth, 2 weeks, 6 weeks, and then at 3, 6, 12, 24, and 36 months, longitudinal anthropometric measurements and blood spot collections were conducted. Infant body composition was assessed using air displacement plethysmography (ADP) at 6 weeks and 3 months of age. Breast milk was collected for macronutrients and human milk oligosaccharides (HMO) measurements. Breast milk intake volume was also estimated, as well as sterile breastmilk and infant stool collection for microbiome study.

The human cytokine interleukin (IL)-37 is an anti-inflammatory member of the IL-1 family of cytokines. Transgenic expression of IL-37 in mice protects them from diet-induced obesity and associated metabolic complications including dyslipidemia, inflammation and insulin resistance. The precise mechanism of action leading to these beneficial metabolic effects is not entirely known. Therefore, we aimed to assess in detail the effect of transgenic IL-37 expression on energy balance, including food intake and energy expenditure. Feeding homozygous IL-37 transgenic mice and wild-type (WT) control mice a high-fat diet (HFD; 45% kcal palm fat) for 6 weeks showed that IL-37 reduced body weight related to a marked decrease in food intake. Subsequent mechanistic studies in mice with heterozygous IL-37 expression versus WT littermates, fed the HFD for 18 weeks, confirmed that IL-37 reduces food intake, which led to a decrease in lean body mass, but did not reduce fat mass and plasma lipid levels or alterations in energy expenditure independent of lean body mass. Taken together, this suggests that IL-37 reduces lean body mass by reducing food intake.