Maternal obesity increases the risk for pediatric obesity; however, the molecular mechanisms in human infants remain poorly understood. We hypothesized that mesenchymal stem cells (MSCs) from infants ...born to obese mothers would demonstrate greater potential for adipogenesis and less potential for myogenesis, driven by differences in β-catenin, a regulator of MSC commitment. MSCs were cultured from the umbilical cords of infants born to normal-weight (prepregnancy pp BMI 21.1 ± 0.3 kg/m(2); n = 15; NW-MSCs) and obese mothers (ppBMI 34.6 ± 1.0 kg/m(2); n = 14; Ob-MSCs). Upon differentiation, Ob-MSCs exhibit evidence of greater adipogenesis (+30% Oil Red O stain ORO, +50% peroxisome proliferator-activated receptor (PPAR)-γ protein; P < 0.05) compared with NW-MSCs. In undifferentiated cells, total β-catenin protein content was 10% lower and phosphorylated Thr41Ser45/total β-catenin was 25% higher (P < 0.05) in Ob-MSCs versus NW-MSCs (P < 0.05). Coupled with 25% lower inhibitory phosphorylation of GSK-3β in Ob-MSCs (P < 0.05), these data suggest greater β-catenin degradation in Ob-MSCs. Lithium chloride inhibition of GSK-3β increased nuclear β-catenin content and normalized nuclear PPAR-γ in Ob-MSCs. Last, ORO in adipogenic differentiating cells was positively correlated with the percent fat mass in infants (r = 0.475; P < 0.05). These results suggest that altered GSK-3β/β-catenin signaling in MSCs of infants exposed to maternal obesity may have important consequences for MSC lineage commitment, fetal fat accrual, and offspring obesity risk.
Abstract Background Consistent evidence of an influence of maternal dietary intake during pregnancy on infant body size and composition in human populations is lacking, despite robust evidence in ...animal models. Objective To evaluate the influence of maternal macronutrient intake and balance during pregnancy on neonatal body size and composition, including fat mass and fat free mass. Study Design The analysis was conducted among 1040 mother-offspring pairs enrolled in the prospective pre-birth observational cohort: The Healthy Start Study. Diet during pregnancy was collected using repeated 24 hour dietary recalls (up to 8). Direct measures of body composition were obtained using air displacement plethysmography. The National Cancer Institute measurement error model was used to estimate usual dietary intake during pregnancy. Multivariable partition (non-isocaloric) and nutrient density (isocaloric) linear regression models were used to test the associations between maternal dietary intake and neonatal body composition. Results The median macronutrient composition during pregnancy was 32.2% from fat, 15.0% from protein and 47.8% from carbohydrates. In the partition multivariate regression model, individual macronutrient intake values were not associated with birth weight or fat free mass, but were associated with fat mass. Respectively, 100 kilocalorie increases in total fat, saturated fat, unsaturated fat and total carbohydrates were associated with 4.2 gram (p=0.03), 11.1 gram (p=0.003), 5.9 gram (p=0.04) and 2.9 gram (p=0.02) increases in neonatal fat mass, independent of pre-pregnancy BMI. In the nutrient density multivariate regression model, macronutrient balance was not associated with fat mass, fat free mass or birth weight after adjustment for pre-pregnancy BMI. Conclusions Neonatal adiposity, but not birth weight, is independently associated with increased maternal intake of total fat, saturated fat, unsaturated fat, and total carbohydrates, but not protein, suggesting that most forms of increased caloric intake contribute to fetal fat accretion.
Using data from a longitudinal cohort of children, we examined whether epigenetic age acceleration (EAA) was associated with pubertal growth and whether these associations were mediated by adiposity. ...We examined associations between EAA at approximately 10 years of age with pubertal growth metrics, including age at peak height velocity (PHV), PHV, and sex steroid levels and whether these associations were mediated by measures of adiposity including body mass index (BMI) and MRI-assessed visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Children (n = 135) with accelerated EAA had higher PHV (β 0.018, p = 0.0008) although the effect size was small. The association between EAA and age at PHV was not significant (β - 0.0022, p = 0.067). Although EAA was associated with higher BMI (β 0.16, p = 0.0041), VAT (β 0.50, p = 0.037), and SAT (β 3.47, p = 0.0076), BMI and VAT did not mediate associations between EAA and PHV, while SAT explained 8.4% of the association. Boys with higher EAA had lower total testosterone (β - 12.03, p = 0.0014), but associations between EAA and other sex steroids were not significant, and EAA was not associated with sex steroid levels in girls. We conclude that EAA did not have strong associations with either age at onset of puberty or pubertal growth speed, although associations with growth speed were statistically significant. Studies with larger sample sizes are needed to confirm this pattern of associations.
Extra-articular manifestations of rheumatoid arthritis (RA), potentially due to systemic inflammation, include cardiovascular disease and sarcopenic obesity. Adiponectin, an adipose-derived cytokine, ...has been implicated in inflammatory processes in RA, but little is known regarding its association with inflammation in a pre-clinical period. Therefore, we investigated whether adiponectin was associated with inflammatory markers in individuals at risk for RA, and whether RA-related autoimmunity modifies these associations.
We analyzed samples from 144 first-degree relatives (FDRs) of RA probands, of whom 23 were positive for anti-cyclic citrullinated peptide antibody and/or ≥ 2 rheumatoid factor isotypes (IgM, IgG or IgA). We called this phenotype the 'high risk autoantibody profile (HRP)' as it has been shown in prior work to be >96% specific for future RA. We measured adiponectin, cytokines, and high-sensitivity C-reactive protein (hsCRP). Using linear mixed effects models, we evaluated interaction between HRP positivity and adiponectin on inflammatory markers, adjusting for age, sex, ethnicity, body mass index, pack-years smoking, and use of cholesterol-lowering medications.
In everyone, adiponectin concentration was inversely associated with hsCRP and IL-1β in adjusted models, where a 1% higher adiponectin was associated with a 26% lower hsCRP (p = 0.04) and a 26% lower IL-1β (p = 0.04). Significant interactions between HRP and adiponectin for associations with GM-CSF, IL-6, and IL-9 were detected in fully adjusted models (p = 0.0006, p = 0.006, p = 0.01, respectively). In HRP positive FDRs but not HRP negative FDRs, a 1% higher adiponectin was associated with 97% higher GM-CSF, 73% higher IL-6, and 54% higher IL-9 concentrations.
Adiponectin associates with inflammatory markers, and these associations differ in individuals with a high-risk autoantibody profile compared with those without. The interaction between adiponectin and autoimmunity warrants further investigation into the potential systemic effects of RA-related autoantibodies and adiponectin on inflammation in the absence of clinically apparent RA.
Both lifestyle and metformin interventions can delay or prevent progression to type 2 diabetes mellitus (DM) in people with impaired glucose regulation, but there is considerable interindividual ...variation in the likelihood of receiving benefit. Understanding an individual's 3-year risk of progressing to DM and regressing to normal glucose regulation (NGR) might facilitate benefit-based tailored treatment.
We used the values of 19 clinical variables measured at the Diabetes Prevention Program (DPP) baseline evaluation and Cox proportional hazards models to assess the 3-year risk of progression to DM and regression to NGR separately for DPP lifestyle, metformin, and placebo participants who were adherent to the interventions. Lifestyle participants who lost ≥5% of their initial body weight at 6 months and metformin and placebo participants who reported taking ≥80% of their prescribed medication at the 6-month follow-up were defined as adherent.
Eleven of 19 clinical variables measured at baseline predicted progression to DM, and 6 of 19 predicted regression to NGR. Compared with adherent placebo participants at lowest risk of developing diabetes, participants at lowest risk of developing diabetes who adhered to a lifestyle intervention had an 8% absolute risk reduction (ARR) of developing diabetes and a 35% greater absolute likelihood of reverting to NGR. Participants at lowest risk of developing diabetes who adhered to a metformin intervention had no reduction in their risk of developing diabetes and a 17% greater absolute likelihood of reverting to NGR. Participants at highest risk of developing DM who adhered to a lifestyle intervention had a 39% ARR of developing diabetes and a 24% greater absolute likelihood of reverting to NGR, whereas those who adhered to the metformin intervention had a 25% ARR of developing diabetes and an 11% greater absolute likelihood of reverting to NGR.
Unlike our previous analyses that sought to explain population risk, these analyses evaluate individual risk. The models can be used by overweight and obese adults with fasting hyperglycemia and impaired glucose tolerance to facilitate personalized decision-making by allowing them to explicitly weigh the benefits and feasibility of the lifestyle and metformin interventions.
Recent evidence supports that the maternal gut microbiota impacts the initial infant gut microbiota. Since the gut microbiota may play a causal role in the development of obesity, it is important to ...understand how pre-pregnancy weight and gestational weight gain (GWG) impact the gut microbiota of mothers at the time of delivery and their infants in early life. In this study, we performed 16S rRNA gene sequencing on gut microbiota samples from 169 women 4 days after delivery and from the 844 samples of their infants at six timepoints during the first 2 years of life. We categorized the women (1) according to pre-pregnancy body mass index into overweight/obese (OW/OB, BMI ≥ 25) or non-overweight/obese (BMI < 25) and (2) into excessive and non-excessive GWG in the subset of mothers of full-term singleton infants (N = 116). We compared alpha diversity and taxonomic composition of the maternal and infant samples by exposure groups. We also compared taxonomic similarity between maternal and infant gut microbiota.
Maternal OW/OB was associated with lower maternal alpha diversity. Maternal pre-pregnancy OW/OB and excessive GWG were associated with taxonomic differences in the maternal gut microbiota, including taxa from the highly heritable family Christensenellaceae, the genera Lachnospira, Parabacteroides, Bifidobacterium, and Blautia. These maternal characteristics were not associated with overall differences in the infant gut microbiota over the first 2 years of life. However, the presence of specific OTUs in maternal gut microbiota at the time of delivery did significantly increase the odds of presence in the infant gut at age 4-10 days for many taxa, and these included some lean-associated taxa.
Our results show differences in maternal gut microbiota composition at the time of delivery by pre-pregnancy weight and GWG, but these changes were only associated with limited compositional differences in the early life gut microbiota of their infants. Further work is needed to determine the degree to which these maternal microbiota differences at time of birth with OW/OB and GWG may affect the health of the infant over time and by what mechanism.
The Kelly West Award for Outstanding Achievement in Epidemiology is presented in honor of the memory of Kelly M. West, widely regarded as the "father of diabetes epidemiology." Harry Keen described ...West as characterized by "generosity of spirit, deeply human and humorous, deliberate of address, modest, conciliatory and untiringly persevering. Few people have done so much to change the landscape of diabetes" (1). The award and lecture recognize a leading epidemiologist in the field of diabetes. Dana Dabelea, MD, PhD, received this award at the American Diabetes Association's 77th Scientific Sessions, 9-13 June 2017, in San Diego, CA. She presented the Kelly West Award Lecture, "Diabetes in Youth-Looking Backwards to Inform the Future," on Sunday, 11 June 2017.
Abstract
Endocrine care of pediatric and adult patients continues to be plagued by health and health care disparities that are perpetuated by the basic structures of our health systems and research ...modalities, as well as policies that impact access to care and social determinants of health. This scientific statement expands the Society's 2012 statement by focusing on endocrine disease disparities in the pediatric population and sexual and gender minority populations. These include pediatric and adult lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA) persons. The writing group focused on highly prevalent conditions—growth disorders, puberty, metabolic bone disease, type 1 (T1D) and type 2 (T2D) diabetes mellitus, prediabetes, and obesity. Several important findings emerged. Compared with females and non-White children, non-Hispanic White males are more likely to come to medical attention for short stature. Racially and ethnically diverse populations and males are underrepresented in studies of pubertal development and attainment of peak bone mass, with current norms based on European populations. Like adults, racial and ethnic minority youth suffer a higher burden of disease from obesity, T1D and T2D, and have less access to diabetes treatment technologies and bariatric surgery. LGBTQIA youth and adults also face discrimination and multiple barriers to endocrine care due to pathologizing sexual orientation and gender identity, lack of culturally competent care providers, and policies. Multilevel interventions to address these disparities are required. Inclusion of racial, ethnic, and LGBTQIA populations in longitudinal life course studies is needed to assess growth, puberty, and attainment of peak bone mass. Growth and development charts may need to be adapted to non-European populations. In addition, extension of these studies will be required to understand the clinical and physiologic consequences of interventions to address abnormal development in these populations. Health policies should be recrafted to remove barriers in care for children with obesity and/or diabetes and for LGBTQIA children and adults to facilitate comprehensive access to care, therapeutics, and technological advances. Public health interventions encompassing collection of accurate demographic and social needs data, including the intersection of social determinants of health with health outcomes, and enactment of population health level interventions will be essential tools.
Despite widespread recognition among public health experts that childhood sugar-sweetened beverage consumption should be reduced, doing so has proven to be a challenge. An agent-based model of early ...childhood sugar-sweetened beverage consumption was applied to data from three high-quality, longitudinal cohort studies to gain insight into potentially effective intervention strategies across contexts.
From 2021 to 2023, a single agent-based model design was applied to data sets derived from three separate cohorts of children followed from infancy to childhood, with very different populations and environments (participants recruited in 1999-2002; 2003-2010; and 2009-2014). After assessing its ability to reproduce observed consumption patterns across cohorts, it was used to simulate potential impacts of multiple intervention strategies across contexts.
Interventions reducing home availability of sugar-sweetened beverages consistently had the largest potential effects. Impact differed between cohort settings: a complete decrease in availability resulted in an estimated 87% decrease in overall early childhood consumption for one of the cohorts, compared with 61% and 54% in the others. Reducing availability in center-based child care resulted in substantially greater reduction in one cohort relative to the other two.
There is untapped potential for strategies targeting children's sugar-sweetened beverage consumption in the home, but in some instances, other approaches might also yield meaningful effects. Tailoring approach to setting may be important, and agent-based models can be informative for doing so. This agent-based model has broad generalizability and potential to serve as a tool for designing effective, context-specific strategies to reduce childhood sugar-sweetened beverage consumption.
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