Changes in the maternal nutritional environment during fetal development can influence offspring's metabolic risk in later life. Animal models have demonstrated that offspring of diet-induced obese ...dams develop metabolic complications, including nonalcoholic fatty liver disease. In this study we investigated the mechanisms in young offspring that lead to the development of nonalcoholic fatty liver disease (NAFLD). Female offspring of C57BL/6J dams fed either a control or obesogenic diet were studied at 8 wk of age. We investigated the roles of oxidative stress and lipid metabolism in contributing to fatty liver in offspring. There were no differences in body weight or adiposity at 8 wk of age; however, offspring of obese dams were hyperinsulinemic. Oxidative damage markers were significantly increased in their livers, with reduced levels of the antioxidant enzyme glutathione peroxidase-1. Mitochondrial complex I and II activities were elevated, while levels of mitochondrial cytochrome c were significantly reduced and glutamate dehydrogenase was significantly increased, suggesting mitochondrial dysfunction. Offspring of obese dams also had significantly greater hepatic lipid content, associated with increased levels of PPARγ and reduced triglyceride lipase. Liver glycogen and protein content were concomitantly reduced in offspring of obese dams. In conclusion, offspring of diet-induced obese dams have disrupted liver metabolism and develop NAFLD prior to any differences in body weight or body composition. Oxidative stress may play a mechanistic role in the progression of fatty liver in these offspring.
The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has ...detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring.
Obesity during gestation adversely affects maternal and infant health both during pregnancy and for long afterwards. However, recent work suggests that a period of maternal exercise during pregnancy ...can improve metabolic health of the obese mother and her offspring. This study aimed to identify the physiological and molecular impact of exercise on the obese mother during pregnancy that may lead to improved metabolic outcomes. To achieve this, a 20‐min treadmill exercise intervention was performed 5 days a week in diet‐induced obese female mice from 1 week before and up to day 17 of pregnancy. Biometric, biochemical and molecular analyses of maternal tissues and/or plasma were performed on day 19 of pregnancy. We found exercise prevented some of the adverse changes in insulin signaling and lipid metabolic pathways seen in the liver, skeletal muscle and white adipose tissue of sedentary‐obese pregnant dams (p110β, p110α, AKT, SREBP). Exercise also induced changes in the insulin and lipid signaling pathways in obese dams that were different from those observed in control and sedentary‐obese dams. The changes induced by obesity and exercise were tissue‐specific and related to alterations in tissue lipid, protein and glycogen content and plasma insulin, leptin and triglyceride concentrations. We conclude that the beneficial effects of exercise on metabolic outcomes in obese mothers may be related to specific molecular signatures in metabolically active maternal tissues during pregnancy. These findings highlight potential metabolic targets for therapeutic intervention and the importance of lifestyle in reducing the burden of the current obesity epidemic on healthcare systems.
Obesity during pregnancy negatively affects maternal and infant health both during and after pregnancy. Recent work suggests that a period of maternal exercise can improve metabolic health of the obese mother during pregnancy and that of her children. However, little is known about the changes that occur in the tissues of the exercised obese pregnant mother that may lead to the improved metabolic outcomes in the mother and consequently the child. This study in mice made obese due to a high sugar and fat diet shows that the beneficial effects of exercise on metabolic health in obese mothers relates to changes in specific metabolic signalling pathways in maternal tissues during pregnancy. These findings highlight potential metabolic targets for therapeutic intervention and the importance of lifestyle in reducing the burden of the current obesity epidemic on healthcare systems worldwide.
Obesity and gestational diabetes (GDM) impact fetal growth during pregnancy. Iron is an essential micronutrient needed for energy-intense feto-placental development, but if mis-handled can lead to ...oxidative stress and ferroptosis (iron-dependent cell death). In a mouse model showing maternal obesity and glucose intolerance, we investigated the association of materno-fetal iron handling and placental ferroptosis, oxidative damage and stress signalling activation with fetal growth. Female mice were fed a standard chow or high fat, high sugar (HFHS) diet during pregnancy and outcomes were measured at day (d)16 or d19 of pregnancy. In HFHS-fed mice, maternal hepcidin was reduced and iron status maintained (tissue iron levels) at both d16 and d19. However, fetal weight, placental iron transfer capacity, iron deposition, TFR1 expression and ERK2-mediated signalling were reduced and oxidative damage-related lipofuscin accumulation in the placenta was increased in HFHS-fed mice. At d19, whilst TFR1 remained decreased, fetal weight was normal and placental weight, iron content and iron transporter genes (
Dmt1
,
Zip14
, and
Fpn1
) were reduced in HFHS-fed mice
.
Furthermore, there was stress kinase activation (increased phosphorylated p38MAPK, total ERK and JNK) in the placenta from HFHS-fed mice at d19. In summary, a maternal HFHS diet during pregnancy impacts fetal growth trajectory in association with changes in placental iron handling, ferroptosis and stress signalling. Downregulation of placental iron transporters in HFHS mice may protect the fetus from excessive oxidative iron. These findings suggest a role for alterations in placental iron homeostasis in determining perinatal outcomes of pregnancies associated with GDM and/or maternal obesity.
Graphical Abstract
Abstract
Background and Aims
Several biomarkers of inflammation have been correlated with poor renal outcomes and mortality in DKD. However, an effective, well-tolerated treatment of progressive ...renal disease driven by inflammation has remained elusive. Inhibition of IL-33 may provide a novel opportunity to address this unmet medical need in high-risk patients. Here, we: 1) show that tozorakimab, a high-affinity IL-33-neutralizing mAb, promotes glomerular health in inflammation; 2) describe the clinical study to test tozorakimab in patients with DKD; 3) present participant baseline characteristics; and 4) evaluate inflammation-associated biomarker in FRONTIER-1 and four external validation cohorts.
Method
FRONTIER-1 (NCT04170543) is a phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of tozorakimab in patients with DKD; defined as T2DM with an eGFR of 25-75 mL/min/1.73 m2 and a UACR in the range of 100-3,000 mg/g. All participants are expected to receive an ACEi/ARB for > 6 weeks before the treatment period. Approximately 565 patients from multiple countries will be randomized to four dose levels of tozorakimab, or volume-matched placebo dosed subcutaneously every 28 days over a 24-week treatment period. All participants will receive 10 mg dapagliflozin Day 85-168. The primary objective of the study is to evaluate the effect of tozorakimab on albuminuria. Secondary objectives are to assess the safety and tolerability of tozorakimab with and without SGLT2i, evaluate the effect of tozorakimab in combination with ACEi or ARB with and without SGLT2i on albuminuria, and describe the PK and immunogenicity of tozorakimab. Key exploratory objective is to assess baseline and treatment-response for urine and/or circulating biomarkers of inflammation, including hsCRP, IL-33/sIL1RL1, CCL2, and TNFR-1/2. Biomarker response was, furthermore, evaluated in pre-clinical models of DKD, and respective distributions and risk were assessed in four independent DKD cohorts (N > 200).
Results
Transcriptomic profiling of kidney biopsies from patients with DKD indicated a significant glomerular up-regulation of IL-33. Inhibition of IL-33 signalling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model of DKD. This was associated with improved glomerular endothelial health as indicated by decreased cellular inflammation and reduced release of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNFR-1, and CCL2. Hence, FRONTIER-1 was started in 2019. So far, all trial groups are well-balanced and in line with our expectations for this patient population (N = 574). At baseline, > 95% were receiving ACEi/ARBs and approximately 25% were receiving SGLT2i. The mean eGFR was 47.8 ml/min/1,73 m2 (+/- 14.7) and mean UACR was 765 mg/g (+/- 775). The inflammatory state of participants at baseline was assessed in circulation and urine by hsCRP, TNFR-1 and CCL2 (N > 146). Comparison to independent reference cohorts (N > 200) confirmed elevated risk in DKD patients with high urinary TNFR-1 and CCL2 and showed that 6-week treatment of dapagliflozin did not alter these biomarkers significantly.
Conclusion
Taken together, inhibition of IL-33 may be beneficial in patients with DKD on standard of care, who have elevated biomarkers of inflammation such as TNFR-1 and/or CCL2. This hypothesis is currently being tested in the FRONTIER-1 phase 2b clinical study. To identify the patients most likely to benefit from immunomodulatory treatment with tozorakimab, the study will conduct a retrospective analysis of albuminuria and inflammatory biomarkers. The primary analysis of the study is planned for the second half of 2023.
In developed societies, high‐sugar and high‐fat (HSHF) diets are now the norm and are increasing the rates of maternal obesity during pregnancy. In pregnant rodents, these diets lead to ...cardiovascular and metabolic dysfunction in their adult offspring, but the intrauterine mechanisms involved remain unknown. This study shows that, relative to standard chow, HSHF feeding throughout mouse pregnancy increases maternal adiposity (+30%, P<0.05) and reduces fetoplacental growth at d 16 (–10%, P<0.001). At d 19, however, HSHF diet group pup weight had normalized, despite the HSHF diet group placenta remaining small and morphologically compromised. This altered fetal growth trajectory was associated with enhanced placental glucose and amino acid transfer (+35%, P<0.001) and expression of their transporters (+40%, P<0.024). HSHF feeding also up‐regulated placental expression of fatty acid transporter protein, metabolic signaling pathways (phosphoinositol 3‐kinase and mitogen‐activated protein kinase), and several growth regulatory imprinted genes (Igf2, Dlk1, Snrpn, Grb10, and H19) independently of changes in DNA methylation. Obesogenic diets during pregnancy, therefore, alter maternal nutrient partitioning, partly through changes in the placental phenotype, which helps to meet fetal nutrient demands for growth near term. However, by altering provision of specific nutrients, dietary‐induced placental adaptations have important roles in programming development with health implications for the offspring in later life.—Sferruzzi‐Perri, A N., Vaughan, O. R., Haro, M., Cooper, W. N., Musial, B., Charalambous, M., Pestana, D., Ayyar, S., Ferguson‐Smith, A C., Burton, G. J., Con‐stancia, M., Fowden, A. L., An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory. FASEB J. 27, 3928–3937 (2013). www.fasebj.org
Despite the recent advances in our understanding of the role of lipids, metabolites, and related enzymes in mediating kidney injury, there is limited integrated multi-omics data identifying potential ...metabolic pathways driving impaired kidney function. The limited availability of kidney biopsies from living donors with acute kidney injury has remained a major constraint. Here, we validated the use of deceased transplant donor kidneys as a good model to study acute kidney injury in humans and characterized these kidneys using imaging and multi-omics approaches. We noted consistent changes in kidney injury and inflammatory markers in donors with reduced kidney function. Neighborhood and correlation analyses of imaging mass cytometry data showed that subsets of kidney cells (proximal tubular cells and fibroblasts) are associated with the expression profile of kidney immune cells, potentially linking these cells to kidney inflammation. Integrated transcriptomic and metabolomic analysis of human kidneys showed that kidney arachidonic acid metabolism and seven other metabolic pathways were upregulated following diminished kidney function. To validate the arachidonic acid pathway in impaired kidney function we demonstrated increased levels of cytosolic phospholipase A2 protein and related lipid mediators (prostaglandin E2) in the injured kidneys. Further, inhibition of cytosolic phospholipase A2 reduced injury and inflammation in human kidney proximal tubular epithelial cells in vitro. Thus, our study identified cell types and metabolic pathways that may be critical for controlling inflammation associated with impaired kidney function in humans.
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