Metabolic Disorders In Adulthood Research Articles

Maternal Obesity and Neonatal Metabolic Health: Insights Into Insulin Resistance.

Background Maternal obesity is a global health concern that leads to metabolic alterations in the offspring, making them vulnerable to metabolic disorders in adulthood. Early identification of such neonates would provide opportunities to positively alter modifiable risk factors for non-communicable diseases (NCDs) to prevent their occurrence later in life. Objectives This study aimed to assess and contrast insulin resistance (IR) levels in neonates born to mothers with obesity and those born to healthy, non-obese mothers. Methods This case-control study was conducted after approval from the institutional ethics committee. A total of 98 healthy, non-obese pregnant females were included in Group 1, and 68 obese pregnant females were included in Group 2. The participants were followed up until delivery and cord blood samples were collected after delivery. Neonatal glucose and insulin concentrations were estimated, and indices of IR such as homeostatic model assessment for insulin resistance (HOMA-IR), quantitative insulin-sensitivity check index (QUICKI), and glucose-to-insulin ratio were calculated. Neonatal IR indices and anthropometric measurements were compared between the groups using the Z test and correlated with the maternal pre-pregnancy body mass index (BMI) using Pearson's correlation. Additionally, Pearson's correlations were examined between neonatal IR indices and anthropometric measurements. Statistical significance was set at p <0.05. Results Neonates in Group 2 exhibited significantly higher anthropometric parameters and IR indices than those in Group 1. A statistically significant positive correlation was identified between maternal pre-pregnancy BMI, neonatal anthropometric parameters, and IR. Furthermore, a statistically significant positive correlation was observed between neonatal IR and the anthropometric parameters. Conclusion Neonates born to obese mothers exhibited higher anthropometric parameters and insulin resistance than those born to non-obese, healthy mothers. Assessment of IR at birth can help identify neonates who are at higher risk of developing NCD in later life. Timely promotion of a healthy lifestyle can reduce the occurrence of NCDs in later life.

The Relationship of Body Weight, Exclusive Breastfeeding, MP-ASI and Energy Intake with Stunting in Toddlers

The incidence of stunting in toddlers is a global nutritional problem. Stunting causes delays in fine motor and gross motor development, increases morbidity and mortality rates, and increases the risk of metabolic disorders in adulthood. The aim of this study was to determine the relationship between body weight, exclusive breastfeeding, MP-ASI (weaning foods) and energy intake with stunting in toddlers aged 24-59 months. This research is descriptive analytical with a cross sectional design. The sample consisted of 92 participants selected using simple random sampling technique. Data collected with body weight measurements for birth weight, exclusive breastfeeding and MP-ASI questionnaires, energy intake calculate using daily energy requirements calculator, and stunting incidence questionnaire. Data analysis was carried out using the Chi-square test (P&lt;0.05). The results of the study explain that there is a relationship between body weight (p=0.000), exclusive breastfeeding (p=0.003), MP-ASI (p=0.004) and energy intake (p=0.000) with the incidence of stunting in toddlers aged 24–59 months. The research conclusion is that there is a relationship between body weight, exclusive breastfeeding, complementary foods and energy intake with the incidence of stunting in toddlers aged 24-59 months.

Serum Lipocalin-2 Levels as a Biomarker in Pre- and Post-Pubertal Klinefelter Syndrome Patients: A Pilot Study.

Klinefelter syndrome (KS) is a male genetic disease caused by the presence of an extra X chromosome, causing endocrine disorders mainly responsible for a high rate of infertility and metabolic disorders in adulthood. Scientific research is interested in identifying new biomarkers that can be predictive or prognostic of alterations strictly connected to KS. Lipocalin-2 (LCN-2, also known as NGAL) is a small protein initially identified within neutrophils as a protein related to innate immunity. Serum LCN-2 estimation seems to be a useful tool in predicting the metabolic complications caused by several pathological conditions. However, little is known about its potential role in infertility conditions. The present pilot study aims to investigate the presence of LCN-2 in the serum of a group of pre-pubertal and post-pubertal children affected by KS, compared to healthy controls. We demonstrated for the first time the presence of elevated levels of LCN-2 in the serum of KS patients, compared to controls. This increase was accompanied, in pre-pubertal KS patients, by the loss of correlation with LH and HDL, which instead was present in the healthy individuals. Moreover, in all KS individuals, a positive correlation between LCN-2 and inhibin B serum concentration was found. Despite the limited size of the sample analyzed, our preliminary data encourage further studies to confirm the findings and to extend the study to KS adult patients, to verify the predictive/prognostic value of LCN-2 as new biomarker for metabolic diseases and infertility associated with the pathology.

Risk factors and glycaemic control in small-for-gestational-age infants born to mothers with gestational diabetes mellitus: a case–control study using propensity score matching based on a large population

BackgroundSmall for gestational age (SGA) poses a significant concern for newborns, being linked to neonatal complications and potential metabolic disorders in adulthood, especially when born to mothers with gestational diabetes...

Особенности композиционного состава тела и метаболического профиля у детей с саркопеническим ожирением

Sarcopenic obesity (SO) is characterized by a decrease of lean mass and increase of adipose tissue and is associated with various metabolic disorders in adults. The influence of the body composition on the metabolic profile in obese children remains unclear as yet. The purpose of the research was to assess body composition and metabolic profile in children with sarcopenic obesity Methods used: cross-sectional, single-center study was conducted in Feb. 2020-Jul. 2022 which included 116 children (55 boys, 61 girls) with simple obesity (SDS BMI 2.5 [2.2;2.7]) aged 7 to 17 y/o (average age 14.2 [12.3;15.5] y/o) divided into two groups depending on the presence of sarcopenic obesity. The group with sarcopenic obesity ("SO+") included 56 children (19 boys, 37 girls) with simple obesity (SDS BMI 2.5 [2.2; 2.6]). The control group ("SO-") consisted of 60 children (36 boys, 24 girls) with constitutionally exogenous obesity (SDS BMI 2.5 [2.2; 2.7]) without sarcopenia. Results: children with sarcopenic obesity were characterized by an increase in adipose tissue (39.1% [36.4; 41.9] vs 30.6% [27.6; 32.4]; p&lt;0.0001), decrease in lean mass (55.6 [44.8; 63.7] vs 45.6 [39.5; 49.7] kg; p&lt;0.0001) and skeletal muscle mass decrease (25.0 [19.2; 28.2] vs 19.4 [16.3; 22.4] kg; p&lt;0.0001) - all compared to the "SO-" group. There were no statistically significant differences in the frequency of detection of impaired glucose tolerance (p=0.672), insulin resistance (p=0.871) and non-alcoholic fatty liver disease (p=0.657) in both groups. Conclusion: sarcopenic obesity in children is characterized by a reduction of lean mass and skeletal muscle mass and is not accompanied by changes in the metabolic profile. It makes difficult to stratify metabolic risks in this group of pediatric patients.

Long-Term Effects and Potential Impact of Early Nutrition with Breast Milk or Infant Formula on Glucose Homeostasis Control in Healthy Children at 6 Years Old: A Follow-Up from the COGNIS Study.

There is scarce evidence about early nutrition programming of dynamic aspects of glucose homeostasis. We analyzed the long-term effects of early nutrition on glycemic variability in healthy children. A total of 92 children participating in the COGNIS study were considered for this analysis, who were fed with: a standard infant formula (SF, n = 32), an experimental formula (EF, n = 32), supplemented with milk fat globule membrane (MFGM) components, long-chain polyunsaturated fatty acids (LC-PUFAs), and synbiotics, or were breastfed (BF, n = 28). At 6 years old, BF children had lower mean glucose levels and higher multiscale sample entropy (MSE) compared to those fed with SF. No differences in MSE were found between EF and BF groups. Normal and slow weight gain velocity during the first 6 months of life were associated with higher MSE at 6 years, suggesting an early programming effect against later metabolic disorders, thus similarly to what we observed in breastfed children. Conclusion: According to our results, BF and normal/slow weight gain velocity during early life seem to protect against glucose homeostasis dysregulation at 6 years old. EF shows functional similarities to BF regarding children's glucose variability. The detection of glucose dysregulation in healthy children would help to develop strategies to prevent the onset of metabolic disorders in adulthood.

Obesity due to iatrogenic causes in patients with epilepsy: a systematic review

Over the past few years, research has suggested a link between valproate sodium (VPA) therapy and weight gain. This systematic review investigates the association between obesity and VPA treatment in epilepsy patients. PubMed, Web of Science, Science Direct, EBSCO, SCOPUS, Wiley, and Cochrane Library were used to perform a systematic literature search. Study articles were screened by title and abstract using Rayyan QCRI then a full-text assessment was implemented. A total of 9 studies with 416 patients were included. Valproatetreated adult patients for epilepsy experience weight gain up to obesity while undergoing treatment. Studies investigating the pediatric population reported that obesity in children receiving VPA is widespread. Treatment with VPA is associated with a significant weight gain and related metabolic disorders in adults and children with epilepsy. Leptin and insulin resistance are suggested as the primary mechanisms underlying weight gain with VPA, despite the need for extensive research into the mechanisms underlying their development in patients taking the medication.

OR24-5 Zebrafish in Utero Glucose Exposure Induces Lipid Dysregulation That Is Abrogated by Acetyl CoA Carboxylase or Glycolysis Inhibition

Abstract Background and Aim One in ten pregnancies suffer from Gestational Diabetes Mellitus (GDM). GDM exposes fetus to high uterine glucose that causes fetal hyperglycemia. At birth Fetal hyperglycemia results in hypoglycemia, macrosomia, and larger than normal infants and these infants are predisposed to a number of metabolic disorders such as obesity, Type 2 Diabetes and non-alcoholic fatty liver disease (NAFLD) in adulthood. Although in-utero glucose exposure provides evidence for fetal lipid dysregulation linked to metabolic disorders in adults, the molecular mechanisms are still unclear. Increase in circulating insulin and glucose are implicated in the enhanced activation of hepatic De novo lipogenesis (DNL) in dyslipidemia, hence, we aim to investigate the potential beneficial effect of the pharmacological inhibition of DNL or glycolysis in our well-characterized zebrafish model of fetal hyperglycemia that mimics the metabolic disorders in human GDM against lipid derangement mediated by excess glucose in embryos in a short term and avoid the long-term outcome of obesity. Methods We developed a zebrafish model of fetal hyperglycemia by exposing embryos to high glucose (4.5% w/v) during the last day of embryogenesis from 96 to 120 hours post-fertilization (hpf). Glucose level was detected in embryo homogenates by glucometer. Insulin expression was visualized by whole-mount in-situ Hybridization. Gene expression of glycolytic (Hexokinase) and lipogenic [Acetyl-CoA Carboxylase (acca)] markers by RT-qPCR and malonyl CoA levels (product of DNL) by ELISA were also assessed. Lipid accumulation was detected by Oil-Red-O staining (ORO) and quantified by spectrophotometry. Pharmacological intervention using metformin or ND646 (known inhibitors of acca) or 2-Deoxyglucose, 2DG (Known inhibitor of Hexokinase) with glucose for 24hours were utilized to attenuate fetal hyperglycemia-mediated lipid accumulation in embryos. Results Zebrafish embryos exposed to high glucose for 24 hours are transiently hyperglycemic while normoglycemia is restored 24 hours after removal from glucose media. At 120 hpf embryos exposed to high-glucose demonstrated increased insulin, hexokinase, and acca expression compared to untreated controls. We also observed a significant reduction in malonyl CoA levels in ND 646 and metformin cotreated embryos with glucose compared to controls. Interestingly, quantification of ORO staining revealed a significant increase in lipid deposition in glucose treated embryos compared to controls at 120 hpf (0.2±0.01 vrs 0.13±0.005), which was significantly attenuated in embryos co-treated with glucose and 2-DG- (0.15±0.003) or metformin- (0.11±0.007) compared to glucose-treated embryos. Similarly, a moderate reduction in ORO staining was observed in embryos that were co-treated with glucose and ND646 (0.17 ± 0.006). Conclusion and significance Together our results show that embryonic glucose exposure leads to increased lipid accumulation which can be rescued by blocking glycolysis or de novo lipogenesis. Intervening glycolysis and de novo lipogenesis could be a promising therapeutic approach for modulating fetal hyperglycemia-related lipid dysregulations. Presentation: Monday, June 13, 2022 12:00 p.m. - 12:15 p.m.

Network exploration of gene signatures underlying low birth weight induced metabolic alterations.

This study explored underlying gene signatures of low birth weight (LBW) by analyzing differentially expressed genes (DEGs) between LBW and normal birth weight (NBW) subjects. Subjects with different birth weight was collected from GEO database. P < .05 and | logFC | ≥ 1.0 were used for screening DEGs. David (2021 Update) was used to perform GO annotation and KEGG signaling pathway enrichment analysis. The protein-protein interaction network of DEGs was constructed using the STRING database, in which hub genes were mined through Cytoscape software. A total of 326 DEGs were identified, including 287 up-regulated genes and 39 down-regulated genes. The GO biological processes enriched by DEGs mainly involved epidermal growth, keratinization and intermediate fibrous tissue. The DEGs were significantly enriched in intracellular insoluble membranes, desmosomes and extracellular space. Their molecular functions mainly focused on structural molecular activity, structural components of epidermis and structural components of cytoskeleton. PI3K/AKT signaling pathway and tight junction were highlighted as critical pathways enriched by DEGs. Ten hub genes which included KRT14, EGF, DSP, DSG1, KRT16, KRT6A, EPCAM, SPRR1B, PKP1, and PPL were identified from the constructed protein-protein interaction network. A total of 326 DEGs and 10 hub genes were identified as candidates for metabolic disorders in LBW individuals. Our results indicated PI3K/AKT signaling pathway as an intrauterine adaptive mechanism for LBW individuals. We observed activated PI3K/AKT pathway in LBW individuals, which would promote growth and development at the early stage of life, but adversely introduce extra metabolic stress and thereby potentially induce metabolic disorders in adulthood.

A single respiratory tract infection early in life reroutes healthy microbiome development and affects adult metabolism in a preclinical animal model

In adult animals, acute viral infections only temporarily alter the composition of both respiratory and intestinal commensal microbiota, potentially due to the intrinsic stability of this microbial ecosystem. In stark contrast, commensal bacterial communities are rather vulnerable to perturbation in infancy. Animal models proved that disruption of a balanced microbiota development e.g., by antibiotics treatment early in life, increases the probability for metabolic disorders in adults. Importantly, infancy is also a phase in life with high incidence of acute infections. We postulated that acute viral infections in early life might pose a similarly severe perturbation and permanently shape microbiota composition with long-term physiological consequences for the adult host. As a proof of concept, we infected infant mice with a sub-lethal dose of influenza A virus. We determined microbiota composition up to early adulthood (63 days) from small intestine by 16S rRNA gene-specific next-generation sequencing. Infected mice underwent long-lasting changes in microbiota composition, associated with increase in fat mass. High-fat-high-glucose diet promoted this effect while co-housing with mock-treated animals overwrote the weight gain. Our data suggest that in the critical phase of infancy even a single silent viral infection could cast a long shadow and cause long-term microbiota perturbations, affecting adult host physiology.

Gestational Nutrition as a Predisposing Factor to Obesity Onset in Offspring: Role for Involvement of Epigenetic Mechanism.

Maternal lifestyle has been implicated as a predisposing factor in the development of metabolic disorders in adulthood. This lifestyle includes the immediate environment, physical activity and nutrition. Maternal nutrition has direct influence on the developmental programming through biochemical alterations and can lead to modifications in the fetal genome through epigenetic mechanisms. Imbalance in basic micro or macro nutrients due to famine or food deficiency during delicate gestational periods can lead to onset of metabolic syndrome including obesity. A major example is the Dutch famine which led to a serious metabolic disorder in adulthood of affected infants. Notably due to gene variants, individualized responses to nutritional deficiencies are unconventional, therefore intensifying the need to study nutritional genomics during fetal programming. Epigenetic mechanisms can cause hereditary changes without changing the DNA sequence; the major mechanisms include small non-coding RNAs, histone modifications and most stable of all is DNA methylation. The significance association between obesity and DNA methylation is through regulation of genes implicated in lipid and glucose metabolism either directly or indirectly by hypomethylation or hypermethylation. Examples include CPT1A, APOA2, ADRB3 and POMC. Any maternal exposure to malnutrition or overnutrition that can affect genes regulating major metabolic pathways in the fetus, will eventually cause underlying changes that can predispose or cause the onset of metabolic disorder in adulthood. In this review, we examined the interaction between nutrition during gestation and epigenetic programming of metabolic syndrome.

Histomorphometric and oxidative evaluation of the offspring's testis from type 2 diabetic female rats treated with metformin and pentoxifylline.

Type 2 diabetes mellitus (T2D) during pregnancy is characterized by high levels of reactive oxygen species and pro-inflammatory factors in the placenta. Once these reactive species reach the foetus, they trigger physiological adaptations that allow the foetus to survive, but programme the organism to develop metabolic disorders in adulthood. The male reproductive system is highly susceptible to foetal programming. This study aimed to investigate the effects of intrauterine exposure to T2D on testicular histomorphometry and redox homeostasis of adult rats and evaluate the effects of maternal treatment with metformin and pentoxifylline. Female rats were induced to T2D, then treated with metformin and pentoxifylline, or co-treated with both drugs. The females were mated, the male offspring were sacrificed on postnatal day 90, and the testicles were collected for analysis. Metformin protected the tubular compartment, with the maintenance of the Sertoli cell population and daily sperm production. Pentoxifylline attenuated the effects of diabetes on Leydig cells, in addition to stimulating testosterone production and lowering lipid peroxidation. Intrauterine exposure to T2D results in important testicular alterations that compromise gonadal function, and the co-treatment with metformin and pentoxifylline may represent a promising therapy that attenuates these effects by combining the positive influences in both the tubular and interstitial compartments of the testicular parenchyma.

Intrauterine Growth-Restricted Piglets Are Predisposed to Develop Metabolic Disorders in Adulthood When Fed With Parenteral Nutrition in the Neonatal Period

ObjectivesTotal parenteral nutrition (TPN) is lifesaving yet non-normal nutrition regimen during the neonatal period. However, studies have shown that TPN feeding early in life can permanently alter metabolism at later ages. Moreover, intrauterine growth restricted (IUGR) neonates also have a higher risk of developing metabolic diseases (such as obesity and dyslipidemia) in later life. Because a substantial proportion of IUGR neonates receive TPN in early life, we wondered if the metabolic effects of feeding TPN early in life would exacerbate these effects of IUGR? We hypothesized that feeding TPN to IUGR neonates would aggravate the risk of developing obesity and dyslipidemia in adulthood.MethodsSixteen normal weight female piglets (7 d old) were randomized to sow-fed (SF) or early TPN (TPN-CON); 8 (IUGR or runt) piglets were fed TPN as a third group (TPN-IUGR). After 2 weeks of TPN or suckling, all pigs were fed a normal grower diet for 8 mo. At 8 mo, catheters were implanted and in vivo metabolic tests were conducted.ResultsTPN-IUGR pigs demonstrated catch-up growth by 4 mo, and body weights were not different among groups at 8 mo. The metabolic effects of feeding TPN persisted into adulthood, as indicated by higher postprandial plasma triglycerides (TG) and fasting plasma non-esterified fatty acids (NEFA), compared to SF (P < 0.05). IUGR exacerbated TPN-induced risk for diseases by worsening obesity outcomes with greater subcutaneous fat deposition (P < 0.05) and greater ectopic TG deposition in the liver (P < 0.05) and muscle (P < 0.05). Furthermore, IUGR led to dyslipidemia as indicated by higher cholesterol in fasted plasma LDL (P < 0.05), slower postprandial TG clearance (P < 0.05), higher fasting plasma NEFA (P < 0.001) and higher plasma dimethylglycine (P < 0.05), compared to the TPN-CON. IUGR pigs had greater VLDL secretion, as suggested by higher microsomal transfer protein mRNA (P < 0.05). Early TPN programmed reduced lipogenesis, as indicated by lower fatty acid synthase mRNA (P < 0.05), compared to SF.ConclusionsCollectively, these findings conclude that although TPN is a lifesaving measure, feeding TPN to IUGR neonates has long-term metabolic consequences predisposing them to develop metabolic disorders in adulthood.Funding SourcesCanadian Institutes of Health Research.

1184-P: Adolescent Growth Spurt and Type 2 Diabetes Risk in an American Indian Population

Background: Some studies suggest that earlier pubertal development is associated with obesity and metabolic disorders in adulthood, but whether accelerated adolescent linear growth spurt influences type 2 diabetes (T2D) in populations at high risk of diabetes is unclear. Aim: To examine associations of age at initiation of the adolescent growth spurt (i.e., take-off) (ATO) , velocity at take-off (VTO) , and age at peak velocity (APV) with T2D incidence. Methods: Height measurements obtained from a longitudinal study of diabetes in American Indians were used to estimate biological growth parameters using the Preece-Baines growth model I, a parametric model of the human growth curve. Diabetes incidence was analyzed among individuals who had ≥ 4 height examinations at ages 5-17 years and who remained nondiabetic at first examination after age 18. Participants were followed until diabetes developed or last examination. Associations of growth parameters with diabetes incidence were analyzed by Poisson regression. Results: Among 649 originally nondiabetic participants, 135 females and 82 males developed diabetes in a median follow-up of years. With adjustment for age, birth date and maternal diabetes, younger ATO and APV were associated with T2D incidence in males (incidence rate ratio (IRR) =1.75 per year, 95% CI, 1.23, 2.50; and IRR=1.33, 95% CI, 1.01, 1.75, respectively) but not in females (IRR=0.93, 95% CI, 0.75, 1.16; and IRR=1.04, 95% CI, 0.86, 1.26, respectively) . Higher VTO was associated with T2D incidence in males (IRR=1.80 per cm/y, 95% CI, 1.15, 2.81) but not in females (IRR=1.15, 95% CI, 0.88, 1.50) . With further adjustment for adult and childhood BMI and fasting insulin, the associations were attenuated for APV and VTO but remained significant for ATO in males. Conclusion: Our findings suggest that an early and accelerated adolescent growth spurt is a risk factor for T2D, at least in males. These associations are only partially explained by measures of adiposity and insulinemia. Disclosure M.J.Ramirez-luzuriaga: n/a. S.Kobes: None. M.Sinha: None. W.C.Knowler: None. R.L.Hanson: None.

Intergenerational Inheritance of Altered Metabolism Phenotypes After Early‐life Stress in Caenorhabditis elegans

Environmental stress experienced during critical periods of animal development has been shown to impact adult phenotypes through changes in behavior or physiology. In humans, undernutrition in utero can lead to obesity and metabolic disorders in adulthood that can be inherited for two generations in the absence of the original stress. However, how particular stresses can result in tissue‐specific changes in target gene expression, and how that gene expression can be inherited, is not well understood. We have established Caenorhabditis elegans nematodes as a model system to investigate the molecular mechanisms that regulate environmental programming of gene expression. C. elegans larvae experiencing early‐life stress (starvation or crowding) may enter the stress resistant, developmentally arrested dauer stage. When environmental conditions improve, larvae will exit dauer and proceed with reproductive development (postdauers, PD). In previous work, we have shown using RNA‐Seq that hermaphrodites that experienced starvation‐induced dauer (PDStv) exhibited significant changes in gene expression compared to continuously fed animals (control, CON), most notably a downregulation of germline‐expressed genes and upregulation of genes with functions in fatty acid metabolism. These changes in gene expression correlated with production of fewer progeny and a decrease in stored intestinal lipids by Oil Red O (ORO) staining in PDStv adults compared to controls. The observed reduction in fecundity in PDStv hermaphrodites was dependent on functional Δ9‐desaturase genes, fat‐5, fat‐6, and fat‐7,as well as the DAF‐12/VDR steroid signaling pathway, indicating a connection between the starvation‐induced metabolism changes and fertility. Interestingly, embryos of PDStv hermaphrodites contained significantly more lipids compared to control embryos, suggesting that PDStv adults prioritize lipid production for reproduction rather than somatic maintenance after dauer exit. We next examined the lipid storage F1 and F2 generation adults using ORO staining, and found that F1 progeny of PDStv adults have significantly increased lipid storage compared to controls. This difference in lipid storage is reset in the F2 generation. Additionally, inheritance of the altered metabolism in F1 adults is dependent upon PRG‐1/PIWI and HRDE‐1/AGO siRNA pathways. In recent work, we are further investigating the connection between metabolism and fecundity of an animal that experienced early‐life stress. We examined the progeny number of PDStv adults that were cultivated on E. coli OP50 supplemented with different fatty acid molecules. We observed that supplementation with oleic acid (OA) resulted in a significant increase in progeny number compared to animals fed only E. coli, while other fatty acids resulted in no change or a decrease in progeny number. Furthermore, the OA‐dependent increase in progeny number required the Δ9‐desaturase FAT‐7, as well as the DAF‐12/VDR steroid signaling pathway, suggesting that OA may be modifying the starvation‐induced phenotypes of PDStv adults. Together, these results suggest that OA may be acting as a signaling molecule to modulate reproductive plasticity through regulation of the DAF‐12/VDR steroid signaling pathway in response to environmental conditions.

Zebrafish model of in utero glucose exposure alters developmental programming that leads to life‐long metabolic consequences

Background and AimOne in ten pregnancies in the US, suffers from Gestational Diabetes Mellitus (GDM). Offspring born to mothers who have GDM have a higher risk of developing Obesity, Type 2 diabetes and Non‐alcoholic fatty liver disease later in life. Although in utero glucose exposure provides evidence for developmental programming leading to metabolic disorders in adults, the molecular mechanisms are still unclear. We aim to understand the mechanisms implicated in developmental programming and their associated adult outcomes in a well‐established zebrafish model of fetal hyperglycemia that mimics the metabolic disorders in human GDM.MethodsWe developed a zebrafish model of fetal hyperglycemia by exposing embryos to high glucose (4.5% w/v) during the last day of embryogenesis from 96 to 120 hours post fertilization. Glucose level was detected in embryos and larvae homogenates and in adult serum by glucometer. Body composition was determined in adults by EchoMRI, gene expression of glycolytic, lipogenic (Acetyl‐CoA Carboxylase (acca) and mitochondria biogenesis (Peroxisome proliferator‐activated receptor‐gamma coactivator [PGC‐1α/β) markers were quantified by RT‐qPCR and acca by western blot. Lipid accumulation was detected by Oil‐Red‐O staining (ORO) and quantified by spectrophotometry. Triglyceride and cholesterol levels (ELISA), adiposity (Nile red staining) and mitochondrion number (mitotracker staining) were also evaluated. We also assessed if co‐administration of metformin or ND646 (known inhibitors of acca) with glucose can attenuate fetal hyperglycemia‐mediated metabolic outcomes.ResultsZebrafish embryos exposed to high glucose for 24 hrs are transiently hyperglycemic while normoglycemia is restored after glucose exposure. Larvae and adults with embryonic glucose exposure are normoglycemic. Embryos showed an upregulation of hexokinase and pyruvate Kinase expression when assessed at 120 hpf, but no change in expression was detected in larvae. Embryos exposed to glucose showed increased lipid accumulation by ORO staining (0.22 ±0.01 Vs 0.17±0.01) while larvae showed a 5‐fold increase in adiposity. Adult fish develop obesity characterized by increased BMI (0.83±26.34 Vs. 0.60± 33.89) kg/m2 and fat mass (12.07± 2.92 Vs 3.4± 0.4) g. Embryos showed increase in both acca mRNA expression (3‐folds) and activation (decreased phosphorylation). Interestingly, acca expression remained increased in larvae while glycemia was normal. Moreover, there was a significant increase in cholesterol (57.92± 0.7 Vs 34.8±1.01 µM) and triglyceride levels in glucose exposed embryos compared to controls (4.1± 0.75 Vs 0.98±0.27 µM). Our data in embryos revealed an increase in mitochondria number validated by an increase in the expression of PGC‐1α/β. Finally, ORO staining showed that embryonic lipid accumulation was decreased to normal levels, by metformin or ND646 exposure when co‐administered with glucose.Conclusion and significanceTogether our results show that embryonic glucose exposure alters developmental programming, including lipid homeostasis dysregulation that is persistent in larvae and adult. However, it can be rescued by pharmacological approaches.

Comparative Analysis of Gene Expression Profiles in the Adipose Tissue of Obese Adult Mice With Rapid Infantile Growth After Undernourishment In Utero.

Rapid infantile growth (RG) markedly increases the risk of obesity and metabolic disorders in adulthood, particularly among neonates born small. To elucidate the molecular mechanisms by which RG following undernourishment in utero (UN) contributes to the deterioration of adult fat deposition, we developed a UN mouse model using maternal energy restriction, followed by RG achieved by adjustments to 4 pups per litter soon after birth. A high-fat diet (HFD) was fed to weaned pups treated or not (Veh) with tauroursodeoxycholic acid (TU). UN-RG pups showed the deterioration of diet-induced obesity and fat deposition, which was ameliorated by TU. We performed a microarray analysis of epididymal adipose tissue and two gene enrichment analyses (NN-Veh vs UN-RD-Veh and UN-RG-Veh vs UN-RG-TU). The results obtained identified 4 common gene ontologies (GO) terms of inflammatory pathways. In addition to the inflammatory characteristics of 4 GO terms, the results of heatmap and principal component analyses of the representative genes from 4 GO terms, genes of interest (GOI; Saa3, Ubd, S100a8, Hpx, Casp1, Agt, Ptgs2) selected from the 4 GO terms, and immunohistochemistry of macrophages collectively suggested the critical involvement of inflammation in the regulation of fat deposition in the responses to UN and TU. Therefore, the present results support the ‘Developmental Origins of Metaflammation’, the last word of which was recently proposed by the concept of metabolic disorders induced by low-grade systemic inflammation.

Adrenal suppression in patients with chronic obstructive pulmonary disease treated with glucocorticoids: Role of specific glucocorticoid receptor polymorphisms.

Single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids, and thus may alter the therapeutic effects of glucocorticoids. We investigated the prevalence of adrenal suppression after treatment with glucocorticoids and evaluated whether GR SNPs were associated with altered risks of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD). In an observational prospective cohort study, we recruited 78 patients with severe COPD receiving 5 days glucocorticoid treatment for an exacerbation of COPD. In total, 55% of these patients were also receiving regular inhaled corticosteroids (ICS). Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK, and 9β SNPs. The prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 30 days after glucocorticoid treatment was 4/78 (5%). There was no difference between carriers and non-carriers of the polymorphisms (Bcl1, 9β, ER22/23K, and N363S) in corticotropin stimulated plasma-cortisol concentrations. In the haplotype analyses, we included the 50 patients who had a high-sensitivity (76%), a low-sensitivity (4%), or a wild-type (20%) GR haplotype. There was no difference in the frequency of adrenal suppression or metabolic disorders between the two stratified groups: (a) high-sensitivity (Bcl1 and/or N363S) haplotypes vs. (b) low-sensitivity (9β and/or ER22/23K) plus wild-type haplotypes (p > 0.05). Carriers of the high-sensitivity GR gene haplotype exhibited a steeper decline in stimulated P-cortisol with increased ICS dose (slope, -1.35 vs. 0.94; p = 0.17), compared to the group with low-sensitivity or wild-type haplotypes, respectively. In total, 5% of patients exhibited insufficient adrenal function. The Bcl1 and N363S polymorphisms did not seem to increase the risk of glucocorticoid suppression or metabolic disorders in adults treated with glucocorticoids for COPD exacerbations.

Effects of combined training on metabolic profile, lung function, stress and quality of life in sedentary adults: A study protocol for a randomized controlled trial

BackgroundBoth physical inactivity and sedentary behavior are considered modifiable risk factors for chronic diseases and all-cause mortality. Adult office-workers spend most of their working day in sedentary behaviors, so they are particularly at high risk of developed chronic diseases (e.g., cardiovascular diseases, metabolic disorders like diabetes mellitus, …). It seems important to promote behavioral changes that could prevent or delay metabolic disease development. Evidence supports the use of exercise programs, however, to date there are several knowledge gaps and inconsistencies in the literature regarding the effects of Combined Training (i.e., aerobic plus resistance training) in sedentary healthy adults. This paper outlines an RCT designed to evaluate the effects of a 16-week combined training program on biochemical and immune markers of metabolic disease, lung function, salivary stress hormones and subjective quality of life (primary outcomes), as well as on body composition and physical fitness (secondary outcomes) in sedentary middle-aged office-workers. Furthermore, we aimed to assess the associations between the changes promoted by the exercise program and the different variables studied.Methods and designThis is a single-blinded two-arm RCT with parallel groups. A minimum of healthy 40 office-workers aged 40–64 years will be recruited to engage in a 16-week intervention study. After baseline assessments, participants will be randomized to one of the two groups: (1) combined training group or (2) control group. Baseline assessments will be repeated after 8 weeks of intervention (mid-testing) and upon completion of the intervention (post-testing).DiscussionThis RCT involves a multi-disciplinary approach and seems to be a relevant contribution to understanding the potential role of combined training in improving the metabolic profile, lung function, stress, and quality of life in adults. The results can provide important insights for clinical recommendations and for the optimization of strategies to prevent metabolic disorders in adults with sedentary jobs.Trial registrationThis trial is registered with ClinicalTrials.gov (registration number: NCT04868240; date of registration April 30, 2021).

Influence of intranasally administered insulin on metabolic and hormonal parameters in adult male rats, impaired due to three-day fasting in the early postnatal period

Temporary cessation or restriction of breastfeeding can lead to metabolic disorders in adulthood. However, data on the effect of fasting in the early postnatal period on the functions of the endocrine system in adulthood are rare and contradictory. Approaches for the correction of metabolic and hormonal disorders caused by premature cessation of breastfeeding have not been developed yet. The aim of the work was to study the metabolic and hormonal parameters and changes in the hormonal status of the gonadal and thyroid systems in 10-month-old male rats with interruption of breastfeeding on days P19-P21, as well as to evaluate the restorative effect on them of four weeks of treatment with intranasal insulin (II) administered in the postnatal period (P28-P55) or in adulthood (P183-P210). Lactation interruption has been induced by treatment of lactating females with bromocriptine (10 mg/day/rat, P19-P21). Male rats with temporary cessation of breastfeeding developed characteristic signs of the metabolic syndrome (obesity, dyslipidemia, impaired glucose tolerance, hyperleptinemia), decreased levels of testosterone and thyroid hormones (fT4, tT3) and weakened the synthesis of testosterone and thyroxine, stimulated respectively by GnRH and thyroliberin. This was due to a decrease in the sensitivity of the testes to luteinizing hormone (LH) and the thyroid gland to thyroid-stimulating hormone (TSH). Treatment with II in early ontogenesis reduced body weight and fat, improved lipid profile, sensitivity to insulin, leptin, LH and TSH, restored the levels of testosterone and thyroid hormones and their stimulation by releasing factors. Treatment with II in adulthood normalized the levels of testosterone, thyroid hormones, their stimulation by releasing factors, but had a little effect on metabolic and hormonal parameters. The obtained data point to a wide range of metabolic and hormonal disorders in adult male rats with the "neonatal" model of metabolic syndrome and to the effectiveness of various strategies for their correction using long-term II treatment.