scholarly journals Placental Insulin/IGF-1 Signaling, PGC1α, and Inflammatory Pathways are Associated With Metabolic Outcomes at 4-6 years of Age: The ECHO Healthy Start Cohort

2021 ◽  
Author(s):  
Madeline Rose Keleher ◽  
Kathryn Erickson ◽  
Harry A. Smith ◽  
Katerina J. Kechris ◽  
Ivana V. Yang ◽  
...  
Keyword(s):  
Skinfold Thickness ◽  
Healthy Start ◽  
Protein Glycosylation ◽  
Receptor Protein ◽  
Growth Factor Signaling ◽  
Serum Triglycerides ◽  
Placental Function ◽  
Adult Disease ◽  
Cortisol Metabolism ◽  
Metabolic Outcomes

An adverse intrauterine environment is associated with the future risk of obesity and type 2 diabetes. Changes in placental function may underpin the intrauterine origins of adult disease, but longitudinal studies linking placental function with childhood outcomes are rare. Here, we determined the abundance and phosphorylation of protein intermediates involved in insulin signaling, inflammation, cortisol metabolism, protein glycosylation, and mitochondrial biogenesis in placental villus samples from healthy mothers from the Healthy Start cohort. Using MANOVA, we tested the association between placental proteins and offspring adiposity (percent fat mass) at birth (n=109) and infancy (4-6mo, n=104), and adiposity, skinfold thickness, triglycerides, and insulin in children (4-6y, n=66). Placental IGF-1 receptor protein was positively associated with serum triglycerides in children. GSK3β phosphorylation at serine 9, a readout of insulin and growth factor signaling, and the ratio of phosphorylated to total JNK2 were both positively associated with midthigh skinfold thickness in children. Moreover, PGC-1α abundance was positively associated with insulin in children. In conclusion, placental insulin/IGF-1 signaling, PGC-1α, and inflammation pathways were positively associated with metabolic outcomes in 4-6-year-old children, identifying a novel link between placental function and long-term metabolic outcomes.

scholarly journals Placental Insulin/IGF-1 Signaling, PGC1α, and Inflammatory Pathways are Associated With Metabolic Outcomes at 4-6 years of Age: The ECHO Healthy Start Cohort

2021 ◽  
Author(s):  
Madeline Rose Keleher ◽  
Kathryn Erickson ◽  
Harry A. Smith ◽  
Katerina J. Kechris ◽  
Ivana V. Yang ◽  
...  
Keyword(s):  
Skinfold Thickness ◽  
Healthy Start ◽  
Protein Glycosylation ◽  
Receptor Protein ◽  
Growth Factor Signaling ◽  
Serum Triglycerides ◽  
Placental Function ◽  
Adult Disease ◽  
Cortisol Metabolism ◽  
Metabolic Outcomes

An adverse intrauterine environment is associated with the future risk of obesity and type 2 diabetes. Changes in placental function may underpin the intrauterine origins of adult disease, but longitudinal studies linking placental function with childhood outcomes are rare. Here, we determined the abundance and phosphorylation of protein intermediates involved in insulin signaling, inflammation, cortisol metabolism, protein glycosylation, and mitochondrial biogenesis in placental villus samples from healthy mothers from the Healthy Start cohort. Using MANOVA, we tested the association between placental proteins and offspring adiposity (percent fat mass) at birth (n=109) and infancy (4-6mo, n=104), and adiposity, skinfold thickness, triglycerides, and insulin in children (4-6y, n=66). Placental IGF-1 receptor protein was positively associated with serum triglycerides in children. GSK3β phosphorylation at serine 9, a readout of insulin and growth factor signaling, and the ratio of phosphorylated to total JNK2 were both positively associated with midthigh skinfold thickness in children. Moreover, PGC-1α abundance was positively associated with insulin in children. In conclusion, placental insulin/IGF-1 signaling, PGC-1α, and inflammation pathways were positively associated with metabolic outcomes in 4-6-year-old children, identifying a novel link between placental function and long-term metabolic outcomes.

A Novel Small-Molecule Approach To Inhibit Jak2 Tyrosine Kinase Signaling.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1556-1556
Author(s):  
Vaibhav Kapuria ◽  
Geoffrey Bartholomeusz ◽  
Ling-Yuan Kong ◽  
William Bornmann ◽  
Zhenghong Peng ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Target Genes ◽  
Jak2 V617f ◽  
Receptor Protein ◽  
Cytokine Signaling ◽  
Growth Factor Signaling ◽  
Intact Cells ◽  
Stat Signaling ◽  
Specific Proteins

Abstract Jak kinases are non-receptor protein tyrosine kinases that play a pivotal role in cytokine/growth factor signaling through phosphorylation of specific proteins such as the Stat molecules. Activated Stats translocate to the nucleus where they mediate transcription of several target genes involved in cell cycle progression and survival (Bcl-xL, cyclin D1, c-myc, survivin. Many tumors have highly activated Stats that are associated with aberrant Jak2 regulation and recent studies have shown that activating mutations in Jak2 (V617F) play a key role in many myeloproliferative disorders such as polycythemia vera and essential thrombocythemia. Jak inhibitors may be useful in treating many diseases with aberrant Jak2/Stat signaling. The most commonly used inhibitor of Jak2 is the tyrphostin AG490, which inhibits Stat3 activation by preventing its tyrosine phosphorylation. However AG490 has limited in vivo efficacy and must be administered at high concentrations (>50 μM) for anti-tumor effects. We describe here a new class of compounds, termed degrasyns, that block Jak2 mediated activation of Stat3 in intact cells at high nM to low μM concentrations. Degrasyns (WP1130/CP2005) did not directly inhibit Jak2 tyrosine kinase activity but suppressed Stat3 activation by reducing the cytoplasmic levels of Jak2. Degrasyn-mediated Jak2 down-regulation was rapid (complete in 2 hrs) and not inhibited by proteasomal, lysosomal, or serine/threonine protease inhibitors. Biochemical studies and confocal microscopy show that degrasyn induces translocation of Jak2 from the plasma membrane/cytosolic fraction into the cytoskeletal fraction and this altered partitioning of Jak2 was associated with loss of cytokine-mediated Stat activation by degrasyn. Jak2 translocation was associated with tyrosine phosphorylation of specific proteins which complex with Jak2. Lyn kinase in the cytoskeletal fraction was highly activated by degrasyn in multiple hematopoetic tumors (multiple myeloma, mantle cell lymphoma, leukemias). Jak2 translocation and Stat inhibition by degrasyn is mechanistically distinct from “classical” Jak2 inhibitors and is not associated with a translocation of other kinases or cytokine signaling molecules in the Jak2 cascade (IL-6R, gp130, Lyn, Btk, Hck, Akt, PI-3K, Erk, Src, Jak1). Degrasyn induces cytoskeletal translocation of both wild-type and mutant (V617F) Jak2 and was associated with induction of apoptosis in HEL cells expressing the Jak2 V617F mutation. These results suggest that degrasyn suppresses Jak/Stat signaling through a unique mechanism involving translocation of Jak2 into a signal transduction incompetent compartment and may be used to investigate a novel form of Stat suppression. Degrasyn may also have anti-tumor effects on cells with aberrant activation of Jak/Stat signaling.

scholarly journals Ethnic Differences in Effects of Maternal Pre-Pregnancy and Pregnancy Adiposity on Offspring Size and Adiposity

2015 ◽  
Vol 100 (10) ◽  
pp. 3641-3650 ◽  
Author(s):  
Xinyi Lin ◽  
Izzuddin M. Aris ◽  
Mya Thway Tint ◽  
Shu E. Soh ◽  
Keith M. Godfrey ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ethnic Differences ◽  
Subsequent Development ◽  
Skinfold Thickness ◽  
Offspring Size ◽  
Offspring Cohort ◽  
Gestational Weight ◽  
Metabolic Outcomes ◽  
Modifiable Factors ◽  
Maternal Adiposity

Context: Maternal adiposity and overnutrition, both before and during pregnancy, plays a key role in the subsequent development of obesity and metabolic outcomes in offspring. Objective: We explored the hypothesis that maternal adiposity (pre-pregnancy and at 26–28 weeks' gestation) and mid-pregnancy gestational weight gain (GWG) are independently associated with offspring size and adiposity in early childhood, and determined whether these effects are ethnicity dependent. Design: In a prospective mother-offspring cohort study (N = 976, 56% Chinese, 26% Malay, and 18% Indian), we assessed the associations of offspring size (weight, length) and adiposity (subscapular and triceps skinfolds), measured at birth and age 6, 12, 18, and 24 mo, with maternal pre-pregnancy body mass index (ppBMI), mid-pregnancy GWG, and mid-pregnancy four-site skinfold thicknesses (triceps, biceps, subscapular, suprailiac). Results: ppBMI and mid-pregnancy GWG were independently associated with postnatal weight up to 2 y and skinfold thickness at birth. Weight and subscapular and triceps skinfolds at birth increased by 2.56% (95% confidence interval, 1.68–3.45%), 3.85% (2.16–5.57%), and 2.14% (0.54–3.75%), respectively for every SD increase in ppBMI. Similarly, a one-SD increase in GWG increased weight and subscapular and triceps skinfolds at birth by 2.44% (1.66–3.23%), 3.28% (1.75–4.84%), and 3.23% (1.65–4.84%), respectively. ppBMI and mid-pregnancy suprailiac skinfold independently predicted postnatal skinfold adiposity up to 2 years of age, whereas only GWG predicted postnatal length. The associations of GWG with postnatal weight and length were present only among Chinese and Indians, but not Malays (P < .05 for interaction). Conclusions: ppBMI and GWG are independent modifiable factors for child size and adiposity up to 2 years of age. The associations are ethnic-dependent, and underscore the importance of ethnic specific studies before generalizing the applicability of risk factors reported in other populations.

scholarly journals Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth

2019 ◽  
Author(s):  
Todd M. Everson ◽  
Marta Vives-Usano ◽  
Emie Seyve ◽  
Andres Cardenas ◽  
Marina Lacasaña ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Birth Outcomes ◽  
Fetal Growth ◽  
Maternal Smoking ◽  
Meta Analysis ◽  
Growth Factor Signaling ◽  
Hormone Activity ◽  
Smoking During Pregnancy ◽  
Placental Function ◽  
Maternal Smoking During Pregnancy

AbstractMaternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. We meta-analyzed the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (7 studies, N=1700, 344 with any MSDP). We identified 1224 CpGs that were associated with MSDP, of which 341 associated with birth outcomes and 141 associated with gene expression. Only 6 of these CpGs were consistent with the findings from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP associated CpGs were enriched for growth-factor signaling, hormone activity, inflammation, and vascularization, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.

scholarly journals Placental Insulin/IGF-1 Signaling, PGC1α, and Inflammatory Pathways are Associated With Metabolic Outcomes at 4-6 years of Age: The ECHO Healthy Start Cohort

Diabetes ◽  
2021 ◽  
pp. db200902
Author(s):  
Madeline Rose Keleher ◽  
Kathryn Erickson ◽  
Harry A. Smith ◽  
Katerina J. Kechris ◽  
Ivana V. Yang ◽  
...  
Keyword(s):  
Healthy Start ◽  
Inflammatory Pathways ◽  
Metabolic Outcomes

scholarly journals Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Todd M. Everson ◽  
Marta Vives-Usano ◽  
Emie Seyve ◽  
Andres Cardenas ◽  
Marina Lacasaña ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Birth Outcomes ◽  
Fetal Growth ◽  
Maternal Smoking ◽  
Meta Analysis ◽  
Growth Factor Signaling ◽  
Environmental Response ◽  
Smoking During Pregnancy ◽  
Placental Function ◽  
Maternal Smoking During Pregnancy

AbstractMaternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.

L-Ascorbic Acid Addition to Chitosan Reduces Body Weight in Overweight Women

2014 ◽  
Vol 84 (1-2) ◽  
pp. 5-11 ◽  
Author(s):  
Eun Y. Jung ◽  
Sung C. Jun ◽  
Un J. Chang ◽  
Hyung J. Suh
Keyword(s):  
Ascorbic Acid ◽  
Body Weight ◽  
Fat Body ◽  
Body Weight Gain ◽  
Skinfold Thickness ◽  
The Body ◽  
Control Group ◽  
Percentage Body Fat ◽  
Overweight Women ◽  
Body Weights

Previously, we have found that the addition of L-ascorbic acid to chitosan enhanced the reduction in body weight gain in guinea pigs fed a high-fat diet. We hypothesized that the addition of L-ascorbic acid to chitosan would accelerate the reduction of body weight in humans, similar to the animal model. Overweight subjects administered chitosan with or without L-ascorbic acid for 8 weeks, were assigned to three groups: Control group (N = 26, placebo, vehicle only), Chito group (N = 27, 3 g/day chitosan), and Chito-vita group (N = 27, 3 g/day chitosan plus 2 g/day L-ascorbic acid). The body weights and body mass index (BMI) of the Chito and Chito-vita groups decreased significantly (p < 0.05) compared to the Control group. The BMI of the Chito-vita group decreased significantly compared to the Chito group (Chito: -1.0 kg/m2 vs. Chito-vita: -1.6 kg/m2, p < 0.05). The results showed that the chitosan enhanced reduction of body weight and BMI was accentuated by the addition of L-ascorbic acid. The fat mass, percentage body fat, body circumference, and skinfold thickness in the Chito and Chito-vita groups decreased more than the Control group; however, these parameters were not significantly different between the three groups. Chitosan combined with L-ascorbic acid may be useful for controlling body weight.

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