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Epidemiological studies demonstrate that maternal obesity and maternal allergy are major risk factors for asthma in offspring. However, the impact of maternal allergy and obesity on offspring lung insulin signaling and allergen responsiveness is not known. To evaluate this, allergic and nonallergic female mice were fed a high-fat diet or low-fat diet from 7 wk before pregnancy until weaning. Neonatal pups were allergen-sensitized and allergen-challenged and then were assessed for obesity, insulin signaling, and allergic inflammation. Compared with pups of nonobese nonallergic mothers, allergen-challenged pups of obese nonallergic mothers, nonobese allergic mothers, and obese allergic mothers had bronchoalveolar lavage (BAL) eosinophilia, with the pups of obese allergic mothers having the highest BAL eosinophilia. These pups also had lower insulin-induced lung AKT phosphorylation, indicating a decrease in lung parenchymal insulin sensitivity. In cross-fostering experiments, allergen-challenged pups exposed to both pre- and postnatal obese allergic mothers had the highest level of BAL eosinophilia. Maternal obesity or allergy increased offspring serum allergen-specific IgE and interleukin-5 that was highest when the mother was both obese and allergic. Also, allergen-challenged pups exposed to both pre- and postnatal obese allergic mothers had the highest level of interleukin-5. In summary, offspring born to obese allergic mothers have decreased lung insulin sensitivity and increased lung allergic inflammation. Interestingly, our data also demonstrate that there is both a pregnancy and postpregnancy aspect of maternal allergy and obesity that enhances allergen responsiveness in offspring., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Maternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalities and metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring's sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health., Methods: We first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit + cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals., Results: We discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance., Conclusions: This study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kok Lim Kua, Maegan capitano reports financial support was provided by National Institutes of Health. Kok Lim Kua reports financial support was provided by March of Dimes Foundation. Kok Lim Kua reports financial support was provided by Riley Children's Foundation. James Ropa reports financial support was provided by National Institutes of Health. Laura Haneline reports financial support was provided by Riley Children's Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Offspring born to mothers with pre-eclampsia (Pre-E) suffer higher risks of adult cardiovascular diseases, suggesting that exposure to an antiangiogenic environment in-utero has a lasting impact on the development of endothelial function. The goal of this study is to test the hypothesis that in-utero exposure to Pre-E results in alterations of angiogenic factors/cytokines that negatively impact vascular development during infancy., Methods: Infants born from mothers with and without Pre-E were recruited and followed up at 6 months. Plasma cytokines, blood pressure, microvessel density, and vascular reactivity were assessed., Results: 6-month-old infants born to mothers with Pre-E had unchanged blood pressure (p = 0.86) and microvessel density (p = 0.57). Vascular reactivity was decreased in infants born to mothers with Pre-E compared to infants born to healthy mothers (p = 0.0345). Interleukin 8 (IL-8) (p = 0.03) and Angiopoeitin-2 (Ang-2) (p = 0.04) were increased in infants born to mothers with Pre-E. We observed that higher IL-8 was associated with lower vascular reactivity (rho = -0.14, p < 0.0001)., Conclusion: At 6 months of age, infants born to mothers with Pre-E had impaired vascular reactivity and higher IL-8 and Ang-2, but similar blood pressure and microvessel density compared to infants born to non-Pre-E mothers., Impact Statement: Changes in cord blood antiangiogenic factors are documented in infants of mothers with pre-eclampsia and may contribute to offspring risks of adult cardiovascular disease. How these factors evolve during early infancy and their correlation with offspring vascular development have not been studied. This study found that 6-month-old infants born to mothers with pre-eclampsia had decreased vascular reactivity, which was correlated with higher IL-8. These findings underscore the lasting impact of maternal pre-eclampsia on offspring vascular development and highlight the need for long-term follow-up in children born to mothers with pre-eclampsia., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The objective of this study was to investigate the influence of α-lipoic acid (LA; R enantiomer) supplementation on maternal and fetal metabolic health in pregnancies complicated by maternal obesity. Forty female Sprague-Dawley rats were randomized to one of 4 treatment groups (n=10/group) throughout prepregnancy (3 weeks) and gestation (20 days): (1) a low calorie control (CON); (2) a high calorie obesity-inducing diet (HC); (3) the HC diet with 0.25% LA (HC+LA) or; (4) the HC diet pair-fed to match the caloric intake of the HC+LA group (HC+PF). On gestation day 20, pregnant rats were placed under anesthesia for collection of maternal/fetal blood and tissues. Compared with the HC group, LA-supplemented mothers demonstrated lower maternal prepregnancy and gestational weight gain (GWG), improved glycemic control (lower homeostatic model assessment for insulin resistance), and higher cholesterol concentrations in serum [high-density lipoprotein cholesterol (HDL-C) and low-and very-low density lipoprotein cholesterol (LDL/VLDL) fractions] and liver. Male and female fetuses from LA-supplemented mothers exhibited lower body weight, improved insulin sensitivity, and evidence of altered lipid metabolism including lower serum HDL-C, lower serum triglyceride (TG), and increased hepatic TG accumulation. Although maternal LA supplementation showed some benefit for both mothers and fetuses with respect to obesity and glycemic control, concern about the potential longer-term implications of liver cholesterol (mothers) and TG accumulation (fetuses) needs further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Todd C Rideout reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Enteral feeding pump systems deliver decreased amounts of macronutrients in human milk to neonates. This study determined the macronutrient loss associated with a bottle-feeding pump system and the effect of manually mixing the human milk during extended feeds., Methods: Macronutrient content from samples of donor human milk was analyzed after simulated extended feeds with a bottle-feeding pump system, using a human milk analyzer. Simulations were repeated using manual mixing of the bottle every 30 min during feeding. The percentage of the baseline was calculated, and one-sample t tests and analysis of variance compared the effect of manual mixing and the duration of feeding on macronutrient delivery., Results: The delivery of fat and energy was lower over time, but manual mixing considerably improved retention. The length of feeding impacted fat delivery, with less fat delivered over time (P < 0.001). Manually mixing significantly increased fat delivery (P < 0.001). Similar results were found for energy, with a significant reduction in energy delivery over time (P < 0.001) and significantly more energy delivered with mixing (P < 0.001). Mixing and the duration of feeding had minimal effect on protein or carbohydrate delivery., Conclusions: Bottle-feeding pump systems are associated with a significant reduction in the delivery of fat and energy of donor human milk. The manual mixing of donor human milk during prolonged feeds is a simple way to improve fat and energy delivery to the neonate., (© 2024 The Author(s). Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Background: Retinopathy of prematurity (ROP) is a disease that affects preterm infants born younger than 30 weeks of gestation. The pathophysiology of ROP involves an initial vaso-obliterative phase followed by vaso-proliferative phase that leads to disease progression. The use of supplemental oxygen during the vaso-proliferative phase of ROP has been associated with reduced disease progression, but how this impacts the need for ROP treatment is unclear. The goal of this study was to compare the rate of laser or intravitreal bevacizumab after implementation of a new supplemental oxygen therapy protocol in preterm infants with stage 2 ROP., Methods: This is a retrospective chart review of preterm infants diagnosed with stage 2 ROP at Riley Hospital for Children between 1/2017 and 12/2022. Patients diagnosed between 1/2017 and 6/2020 were classified as Cohort A, preprotocol implementation. Patients diagnosed from 8/2020 to 12/2022 were classified as Cohort B, postprotocol implementation. In Cohort A, oxygen saturation was kept at 91-95% through the entire hospitalization. In Cohort B, oxygen saturation was increased to 97-99% as soon as Stage 2 ROP was diagnosed. Statistical analyses were performed using chi-square and Student's T test, followed by multivariate analyses to determine the impact of the oxygen protocol on the need for ROP treatment., Results: A total of 211 patients were diagnosed with stage 2 ROP between 1/2017 and 12/2022. Of those patients, 122 were before protocol implementation therapy (Cohort A), and 89 were after implementation of supplemental oxygen protocol (Cohort B). Gestational age was slightly higher in Cohort B (Cohort A 25.3 ± 1.9, Cohort B 25.8 ± 1.84, p = 0.04). There was no difference in birth weight, NEC, BPD, or survival. Cohort B had lesser need for invasive mechanical ventilation and higher days on CPAP during hospitalization. Notably, Cohort A had 67 (55%) patients treated with laser photocoagulation or intravitreal bevacizumab versus 20 (22%) patients in Cohort B (OR 0.19, 0.08-0.40)., Conclusion: The need for laser photocoagulation or intravitreal bevacizumab was significantly decreased in high-risk patients treated with the supplemental oxygen protocol. This result supports the idea that targeted supplemental oxygen therapy to keep saturations between 97 and 99% can reduce disease progression in infants with stage 2 ROP and potentially decrease the burden of additional procedures., (© 2024. The Author(s).)

The prevalence of obesity is increasingly common in the United States, with ~25% of women of reproductive age being overweight or obese. Metaflammation, a chronic low grade inflammatory state caused by altered metabolism, is often present in pregnancies complicated by obesity. As a result, the fetuses of mothers who are obese are exposed to an in-utero environment that has altered nutrients and cytokines. Notably, both human and preclinical studies have shown that children born to mothers with obesity have higher risks of developing chronic illnesses affecting various organ systems. In this review, the authors sought to present the role of cytokines and inflammation during healthy pregnancy and determine how maternal obesity changes the inflammatory landscape of the mother, leading to fetal reprogramming. Next, the negative long-term impact on offspring's health in numerous disease contexts, including offspring's risk of developing neuropsychiatric disorders (autism, attention deficit and hyperactive disorder), metabolic diseases (obesity, type 2 diabetes), atopy, and malignancies will be discussed along with the potential of altered immune/inflammatory status in offspring as a contributor of these diseases. Finally, the authors will list critical knowledge gaps in the field of developmental programming of health and diseases in the context of offspring of mothers with obesity, particularly the understudied role of hematopoietic stem and progenitor cells., Competing Interests: The reviewers 'XH' and 'BG' declared past co-authorships with one of the authors 'MC' and the absence of any ongoing collaboration with any of the authors to the handling editor. KK owns publicly traded stocks (TMO, DHR, DXCM). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Denizli, Capitano and Kua.)

Offspring of obese mothers suffer higher risks of type 2 diabetes due to increased adiposity and decreased β cell function. To date, the sex-differences in offspring islet insulin secretion during early life has not been evaluated extensively, particularly prior to weaning at postnatal day 21 (P21). To determine the role of maternal obesity on offspring islet insulin secretion, C57BL/6J female dams were fed chow or western diet from 4 weeks prior to mating to induce maternal obesity. First, offspring of chow-fed and obese dams were evaluated on postnatal day 21 (P21) prior to weaning for body composition, glucose and insulin tolerance, and islet phasic insulin-secretion. Compared to same-sex controls, both male and female P21 offspring born to obese dams (MatOb) had higher body adiposity and exhibited sex-specific differences in glucose tolerance and insulin secretion. The male MatOb offspring developed the highest extent of glucose intolerance and lowest glucose-induced insulin secretion. In contrast, P21 female offspring of obese dams had unimpaired insulin secretion. Using SAX-HPLC, we found that male MatOb had a decrease in pancreatic heparan sulfate glycosaminoglycan, which is a macromolecule critical for islet health. Notably, 8-weeks-old offspring of obese dams continued to exhibit a similar pattern of sex-differences in glucose intolerance and decreased islet insulin secretion. Overall, our study suggests that maternal obesity induces sex-specific changes to pancreatic HSG in offspring and a lasting effect on offspring insulin secretion, leading to the sex-differences in glucose intolerance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Casasnovas, Damron, Jarrell, Orr, Bone, Archer-Hartmann, Azadi and Kua.)

Introduction: Gut microbiota has been reported to contribute to obesity and the pathology of obesity-related diseases but the underlying mechanisms are largely unknown. Mucosal-associated invariant T (MAIT) cells are a unique subpopulation of T cells characterized by the expression of a semi-invariant T cell receptor (TCR) α chain (Vα19 in mice; Vα7.2 in humans). The expansion and maturation of MAIT cells require the gut microbiota and antigen-presenting molecule MR1, suggesting that MAIT cells may play a unique role in bridging gut microbiota, obesity, and obesity-associated inflammation., Methods: The levels of human MAIT cells from obese patients, as well as mouse MAIT cells from obese mouse models, were determined by flow cytometry. By comparing to controls, we analyzed the change of MAIT cells in obese subjects., Results: We found obese patients had fewer circulating MAIT cells than healthy-weight donors and the difference was more distinct in male patients. Consistently, male mice (but not female mice) have shown reduced MAIT cells in the liver and adipose tissue after a 10-week Western diet compared to mice on a control diet. We also explored the possibility of utilizing high-throughput technology (i.e., quantitative polymerase chain reaction [qPCR]), other than flow cytometry, to determine the expression levels of the invariant TCR of human MAIT cells. But a minimal correlation (R 2  = 0.23, p = .11) was observed between qPCR and flow cytometry data., Conclusion: Our study suggests that there is a sex discrepancy in the impact of obesity on MAIT cells: MAIT cells in male (but not female) humans and male mice are reduced by obesity., (© 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Offspring exposed in utero to maternal diabetes exhibit long-lasting insulin resistance, though the initiating mechanisms have received minimal experimental attention. Herein, we show that rat fetuses develop insulin resistance after only 2-day continuous exposure to isolated hyperglycemia starting on gestational day 18. Hyperglycemia-induced reductions in insulin-induced AKT phosphorylation localized primarily to fetal skeletal muscle. The skeletal muscle of hyperglycemia-exposed fetuses also exhibited impaired in vivo glucose uptake. To address longer term impacts of this short hyperglycemic exposure, neonates were cross-fostered and examined at 21 days postnatal age. Offspring formerly exposed to 2 days late gestation hyperglycemia exhibited mild glucose intolerance with insulin signaling defects localized only to skeletal muscle. Fetal hyperglycemic exposure has downstream consequences which include hyperinsulinemia and relative uteroplacental insufficiency. To determine whether these accounted for induction of insulin resistance, we examined fetuses exposed to late gestational isolated hyperinsulinemia or uterine artery ligation. Importantly, 2 days of fetal hyperinsulinemia did not impair insulin signaling in murine fetal tissues and 21-day-old offspring exposed to fetal hyperinsulinemia had normal glucose tolerance. Similarly, fetal exposure to 2-day uteroplacental insufficiency did not perturb insulin-stimulated AKT phosphorylation in fetal rats. We conclude that fetal exposure to hyperglycemia acutely produces insulin resistance. As hyperinsulinemia and placental insufficiency have no such impact, this occurs likely via direct tissue effects of hyperglycemia. Furthermore, these findings show that skeletal muscle is uniquely susceptible to immediate and persistent insulin resistance induced by hyperglycemia.

Offspring of diabetic mothers are susceptible to developing type 2 diabetes due to pancreatic islet dysfunction. However, the initiating molecular pathways leading to offspring pancreatic islet dysfunction are unknown. We hypothesized that maternal hyperglycemia alters offspring pancreatic islet transcriptome and negatively impacts offspring islet function. We employed an infusion model capable of inducing localized hyperglycemia in fetal rats residing in the left uterine horn, thus avoiding other factors involved in programming offspring pancreatic islet health. While maintaining euglycemia in maternal dams and right uterine horn control fetuses, hyperglycemic fetuses in the left uterine horn had higher serum insulin and pancreatic beta cell area. Upon completing infusion from GD20 to 22, RNA sequencing was performed on GD22 islets to identify the hyperglycemia-induced altered gene expression. Ingenuity pathway analysis of the altered transcriptome found that diabetes mellitus and inflammation/cell death pathways were enriched. Interestingly, the downregulated genes modulate more diverse biological processes, which includes responses to stimuli and developmental processes. Next, we performed ex and in vivo studies to evaluate islet cell viability and insulin secretory function in weanling and adult offspring. Pancreatic islets of weanlings exposed to late gestation hyperglycemia had decreased cell viability in basal state and glucose-induced insulin secretion. Lastly, adult offspring exposed to in utero hyperglycemia also exhibited glucose intolerance and insulin secretory dysfunction. Together, our results demonstrate that late gestational hyperglycemia alters the fetal pancreatic islet transcriptome and increases offspring susceptibility to developing pancreatic islet dysfunction.

Cardiac septal overgrowth complicates 10-40% of births from diabetic mothers, but perplexingly hyperglycemia markers during pregnancy are not reliably predictive. We thus tested whether fetal exposure to hyperglycemia is sufficient to induce fetal cardiac septal overgrowth even in the absence of systemic maternal diabetes. To isolate the effects of hyperglycemia, we infused glucose into the blood supply of the left but not right uterine horn in nondiabetic pregnant rats starting on gestational day 19. After 24 h infusion, right-sided fetuses and dams remained euglycemic while left-sided fetuses were moderately hyperglycemic. Echocardiograms in utero demonstrated a thickened cardiac septum among left-sided (glucose-exposed, 0.592 ± 0.016 mm) compared to right-sided (control, 0.482 ± 0.016 mm) fetuses. Myocardial proliferation was increased 1.5 ± 0.2-fold among left-sided compared to right-sided fetuses. Transcriptional markers of glucose-derived anabolism were not different between sides. However, left-sided fetuses exhibited higher serum insulin and greater JNK phosphorylation compared to controls. These results show that hyperglycemic exposure is sufficient to rapidly induce septal overgrowth even in the absence of the myriad other factors of maternal diabetes. This suggests that even transient spikes in glucose may incite cardiac overgrowth, perhaps explaining the poor clinical correlation of septal hypertrophy with chronic hyperglycemia.

In extremely low birth weight (ELBW) infants, levels of hypercapnia (Paco 2) > 60 mm Hg are considered a risk factor for severe intraventricular hemorrhage (IVH). Since cerebral vasoreactivity depends on arterial pH (apH) rather than Paco 2, we hypothesize that the role of mild-to-moderate hypercapnia (45-60 mm Hg) in the occurrence of severe IVH is modulated by the metabolic component of acid-base status. ELBW infants (n = 580, born < 28 wk gestation, and BW < 1,000 g) were separated into "high-base deficit (BD)" (n = 291) and "low-BD" (n = 289) groups if infants' median BD were > 4 mEq/L or ≤4 mEq/L, respectively. Rates of severe IVH were higher in "high-BD" (16%) than "low-BD" (9%) group. Although adjusted risk for severe IVH increased with higher Paco 2 and higher BD, apH was the sole predictor of severe IVH. In ELBW infants, higher degree of acidemia, rather than hypercapnia per se, during the first 48 hours of life, is associated with higher occurrences of severe IVH., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)