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The effect of HFHS feeding on placental hormone expression in late pregnancy Expression of prolactins/placental lactogen-related genes by the placenta on D16 (A) and D19 (B) of pregnancy in dams fed a control (n > 6, white columns) or HFHS diets (n > 6, black columns). * P < 0.05.
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Key points
In the Western world, obesogenic diets containing high fat and high sugar (HFHS) are commonly consumed during pregnancy, although their effects on the metabolism of the mother, in relation to feto‐placental glucose utilization and growth, are unknown.
In the present study, the consumption of an obesogenic HFHS diet compromised maternal g...
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Androgen deprivation therapy (ADT) for prostate cancer (PC) has detrimental effects on physical function and quality of life (QoL), but the addition of androgen receptor signalling inhibitors (ARSI) on these outcomes is unclear.
Purpose
To compare body composition, physical function, and QoL across progressive stages of PC and non-cance...
Citations
... Maternal liver fat content was assessed as described previously [6]. In brief, 100 mg of homogenized tissue from the left hepatic lobule was added to 1 mL of Folch mixture (chloroform:methanol 2:1), mixed with distilled H 2 O (dH 2 O) and centrifuged at 13,200 rpm for 10 min to obtain the lipid phase. ...
... The abundance of proteins in the maternal liver and placenta was determined as described previously [6]. In brief, 100 mg and 40 mg of frozen liver and placenta, respectively, were individually homogenized in a mix of RIPA buffer and protease inhibitors (Sigma-Aldrich, Saint Louis, MO, USA, R0278). ...
... In women, NAFLD increases the risk of developing preeclampsia and tional diabetes [30,31,57]. Prior work has reported on impaired glucose handling in H fed pregnant dams [6,35,45], but little is known about blood pressure control. Hepa pid accumulation can also lead to the excessive production of free radicals and oxid damage [58,59], which in turn leads to the activation of inflammatory signaling [60] is consistent with the findings of the current study that show a reduced abundance ...
Background: Obesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress, and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity. The aim of this study on mice was to determine the effect of obesity on maternal lipid handling, inflammatory and redox state, and placental oxidative stress, inflammatory signaling, and gene expression relative to female and male fetal growth. Methods: Female mice were fed control or obesogenic high-fat/high-sugar diet (HFHS) from 9 weeks prior to, and during, pregnancy. On day 18.5 of pregnancy, maternal plasma, and liver, placenta, and fetal serum were collected to examine the immune and redox states. The placental labyrinth zone (Lz) was dissected for RNA-sequencing analysis of gene expression changes. Results: the HFHS diet induced, in the dams, hepatic steatosis, oxidative stress (reduced catalase, elevated protein oxidation) and the activation of pro-inflammatory pathways (p38-MAPK), along with imbalanced circulating cytokine concentrations (increased IL-6 and decreased IL-5 and IL-17A). HFHS fetuses were asymmetrically growth-restricted, showing sex-specific changes in circulating cytokines (GM-CSF, TNF-α, IL-6 and IFN-γ). The morphology of the placenta Lz was modified by an HFHS diet, in association with sex-specific alterations in the expression of genes and proteins implicated in oxidative stress, inflammation, and stress signaling. Placental gene expression changes were comparable to that seen in models of intrauterine inflammation and were related to a transcriptional network involving transcription factors, LYL1 and PLAG1. Conclusion: This study shows that fetal growth restriction with maternal obesity is related to elevated oxidative stress, inflammatory pathways, and sex-specific placental changes. Our data are important, given the marked consequences and the rising rates of obesity worldwide.
... Here, we hypothesized that a diet that induces hyperglycaemia and obesity during pregnancy induce oxidative damage, ferroptotic cellular stress responses and dysregulate iron homeostasis in the placenta with consequences for fetal growth. To test this hypothesis, we utilized a wellestablished mouse model, in which mouse dams are fed a western-style high fat and sugar (HFHS) diet just during pregnancy to induce excess adiposity, compromised glucose tolerance and altered insulin sensitivity [46,47]. This study design allowed us to isolate the confounding effects of preexisting obesity and its various associated complications (e.g. ...
... All experiments were performed under the UK Home Office Animals (Scientific Procedures) Act 1986 following ethical review by the University of Cambridge Animal Welfare and Ethical Review Board. The present manuscript is based on a retrospective analysis of a previous and larger experiment, which characterised the effect of the HFHS diet fed only during pregnancy on maternal adiposity, glucose, and insulin handling [46,47]. Hence, this study represents a subset of the original larger cohort. ...
... In the current study we found that fetal growth was reduced at d16 but was then unchanged towards term (d19) in HFHS fed mice. This is largely consistent with the altered pattern of fetal growth trajectory previously analysed in HFHS mouse cohorts [46,47]. Moreover, like previous work using the HFHS mouse model, placental weight was reduced in the HFHS-fed mice [46,[59][60][61]. ...
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
... In addition, the enhanced fat deposition in the HFHS dams may have increased concentrations of leptin, the anorexigenic peptide, consistent with their reduced food intake. Indeed, increased leptin concentrations have been observed in previous studies of pregnant HFHS dams depending on their stage of pregnancy [17,27]. ...
With rising rates of human obesity, this study aimed to determine the relationship between maternal diet-induced obesity, offspring morphometrics, and behavior in mice. Pregnant and lactating female mice fed a diet high in fat and sugar (HFHS) commonly consumed by human populations showed decreased food, calorie, and protein intake but increased adiposity at the expense of lean mass. The pre-weaning body weight of the HFHS offspring was reduced for the first postnatal week but not thereafter, with HFHS female offspring having higher body weights by weaning due to continuing higher fractional growth rates. Post-weaning, there were minor differences in offspring food and protein intake. Maternal diet, however, affected fractional growth rate and total body fat content of male but not female HFHS offspring. The maternal diet did not affect the offspring's locomotor activity or social behavior in either sex. Both the male and female HFHS offspring displayed reduced anxiety-related behaviors, with sex differences in particular aspects of the elevated plus maze task. In the novel object recognition task, performance was impaired in the male but not female HFHS offspring. Collectively, the findings demonstrate that maternal obesity alters the growth, adiposity, and behavior of male and female offspring, with sex-specific differences.
... Consistent with our findings, in diabetic murine C57BL/KsJ-Lep db/+pregnancies, the NRF2 inducer tBHQ reportedly improves maternal glucose tolerance, reduces markers of maternal oxidative stress and enhances postnatal offspring survival [54]. Comparing the phenotype of NRF2 deficient and diet-induced WT obese pregnancies, several studies report maternal obesity increases fetal resorption [55], with delayed fetal growth within the late first and second trimester and normalizing at birth [56][57][58]. In our study, both WT-ObVeh and NRF2KO-ObVeh fetuses were growth restricted. ...
In adverse pregnancy a perturbed redox environment is associated with abnormal early-life cardiovascular development and function. Previous studies have noted alterations in the expression and/or activity of Nuclear Factor E2 Related Factor 2 (NRF2) and its antioxidant targets during human gestational diabetic (GDM) pregnancy, however to our knowledge the functional role of NRF2 in fetal ‘priming’ of cardiovascular dysfunction in obese and GDM pregnancy has not been investigated. Using a murine model of obesity-induced glucose dysregulated pregnancy, we demonstrate that NRF2 activation by maternal sulforaphane (SFN) supplementation normalizes NRF2-linked NQO1, GCL and CuZnSOD expression in maternal and fetal liver placental and fetal heart tissue by gestational day 17.5. Activation of NRF2 in utero in wild type but not NRF2 deficient mice improved markers of placental efficiency and partially restored fetal growth. SFN supplementation was associated with reduced markers of fetal cardiac oxidative stress, including Nox2 and 3-nitrotyrosine, as well as attenuation of cardiac mass and cardiomyocyte area in male offspring by postnatal day 52 and improved vascular function in male and female offspring by postnatal day 98. Our findings are the first to highlight the functional consequences of NRF2 modulation in utero on early-life cardiovascular function in offspring, demonstrating that activation of NRF2 affords cardiovascular protection in offspring of pregnancies affected by redox dysregulation.
... More complicated metabolic phenotypes have also been recorded (Cropley et al., 2016;Dearden et al., 2018;Lawson, 2013;McIntyre et al., 2019;Stephensen, 1999;Tarry-Adkins & Ozanne, 2017;Wei et al., 2003), including the 'double burden' where some nutrients are in excess and others are lacking. Nutritional programming of offspring by the metabolic phenotype of their parents (Blackmore et al., 2014;Fernandez-Twinn et al., 2017;Fernandez-Twinn et al., 2019;Lawson, 2013;Loche et al., 2018;Musial et al., 2017) and dietary intake (Furse et al., 2021;Furse et al., 2022c;Morgan et al., 2020;Watkins et al. 2018;Watkins & Sinclair, 2014;Watkins et al., 2017) is gaining research attention. In mammals, both the parents' metabolic phenotype and nutrient intake shape the development and metabolism of offspring at least two generations hence (Furse et al., 2021;Furse et al., 2022c). ...
Background
Bees provide essential pollination services for many food crops and are critical in supporting wild plant diversity. However, the dietary landscape of pollen food sources for social and solitary bees has changed because of agricultural intensification and habitat loss. For this reason, understanding the basic nutrient metabolism and meeting the nutritional needs of bees is becoming an urgent requirement for agriculture and conservation. We know that pollen is the principal source of dietary fat and sterols for pollinators, but a precise understanding of what the essential nutrients are and how much is needed is not yet clear. Sterols are key for producing the hormones that control development and may be present in cell membranes, where fatty-acid-containing species are important structural and signalling molecules (phospholipids) or to supply, store and distribute energy (glycerides).
Aim of the review
In this critical review, we examine the current general understanding of sterol and lipid metabolism of social and solitary bees from a variety of literature sources and discuss implications for bee health.
Key scientific concepts of review
We found that while eusocial bees are resilient to some dietary variation in sterol supply the scope for this is limited. The evidence of both de novo lipogenesis and a dietary need for particular fatty acids (FAs) shows that FA metabolism in insects is analogous to mammals but with distinct features. Bees rely on their dietary intake for essential sterols and lipids in a way that is dependent upon pollen availability.
... Several studies have reported that, insulin resistance and subsequent development of GDM are influenced by adipose tissue (AT) expansion among other factors (Simas and Corvera, 2014;Aziz et al., 2016;Li et al., 2016;Ngala et al., 2017). During pregnancy, AT expands in response to increased fetal growth (Simas and Corvera, 2014) and can expand further due to consumption of a high fat diet (HFD) (Musial et al., 2017). Fetal growth and HFD mediated AT expansion induce insulin resistance during pregnancy and are pivotal to the development of GDM (Aziz et al., 2016). ...
... 18,19 A pattern of metabolic disorders more evident in mothers was instead observed in mouse models treated with a diet rich in fat and sucrose, where the NAFLD pattern could be associated with a state of low-grade systemic inflammation that may lead to MAFLD features. [18][19][20] EFFECT OF METABOLIC-ASSOCIATED FATTY LIVER DISEASE ON MATERNAL OUTCOMES DURING PREGNANCY: CLINICAL EVIDENCE NAFLD is nowadays considered as an independent risk factor for hypertensive complications, postpartum hemorrhage, and preterm birth. It is mandatory that NAFLD 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 should be considered a high-risk obstetric condition, with clinical implications for counseling about potential obstetric complications and appropriate pregnancy care. ...
Metabolic-associated fatty liver disease (MAFLD), the term proposed to substitute nonalcoholic fatty liver disease, comprises not only liver features but also potentially associated metabolic dysfunctions. Since experimental studies in mice and retrospective clinical studies in humans investigated the association between nonalcoholic fatty liver disease during pregnancy and the adverse clinical outcomes in mothers and offspring, it is plausible that MAFLD may cause similar or worse effects on mother and the offspring. Only a few studies have investigated the possible association of maternal MAFLD with more severe pregnancy-related complications. This article provides an overview of the evidence for this dangerous liaison.
... In collaboration with Dr. Sferrruzzi-Perri, University of Cambridge, they investigated a mouse model with wildtype mice receiving a high fat high sugar (HFHS) diet which resulted in compromised maternal glucose tolerance and insulin sensitivity in association with dysregulated lipid metabolism, thereby mimicking typical GDM symptoms. [90,91] Interestingly, placental tissues from HFHS fed mice and human GDM showed highly comparable expression patterns of iron homeostasis genes. Similar to human GDM, the placentae from HFHS mice also seem to protect the fetus from excessive oxidative iron levels by expressional reduction of placental iron-transporters and iron-regulatory proteins. ...
The TransCure project entitled 'Iron Transporters DMT1 and FPN1' took an interdisciplinary approach combining structural biology, chemistry and physiology to gain new insights into iron transport. Proteins studied included Divalent Metal Transporter 1 (DMT1, SLC11A2), enabling the import of Fe 2+ into the cytoplasm, and the iron efflux transporter Ferroportin (FPN1, SLC40A1). The physiology and pathophysiology, and the mechanisms underlying iron transport in the gut, across the placenta and in bone were investigated. Small molecule high-throughput screening was used to identify improved modulators of DMT1. The characterization of DMT1 inhibitors have provided first detailed insights into the pharmacology of a human iron transport protein. In placental physiology, the identification of the expressional and functional alterations and underlying mechanisms in trophoblast cells clarified the association between placental iron transport by DMT1/FPN1 and gestational diabetes mellitus. In bone, iron metabolism was found to differ between cells of the monocyte/ macrophage lineages, including osteoclasts. Osteoclast development and activity depended on exogenous iron, the expression of high levels of the transferrin receptor (TFR) and low levels of FPN1 suggesting the expression of an 'iron storage' phenotype by these cells. The principles and main findings of the TransCure studies on transmembrane iron transport physiology are summarized in this review.
... For instance, placental glucose transporter is reduced, but fetal growth increased in some models Wang et al., 2021), and glucose and amino acid transporters increased without a change, or even a decrease in fetal weight in others (Song et al., 2017;Wallace et al., 2019). Further work is required to assess the contribution of metabolic changes, like maternal glucose intolerance and dyslipidaemia, to the resultant effects of obesity on placental phenotype Musial et al., 2017Musial et al., , 2019). ...
The placenta is vital for mammalian development and a key determinant of life‐long health. It is the interface between the mother and fetus and is responsible for transporting the nutrients and oxygen a fetus needs to develop and grow. Alterations in placental formation and function, therefore, have consequences for fetal growth and birthweight, which in turn determine perinatal survival and risk of non‐communicable diseases for the offspring in later postnatal life. However, the placenta is not a static organ. As this review summarizes, research from multiple species has demonstrated that placental formation and function alter developmentally to the needs of the fetus for substrates for growth during normal gestation, as well as when there is greater competition for substrates in polytocous species and monotocous species with multiple gestations. The placenta also adapts in response to the gestational environment, integrating information about the ability of the mother to provide nutrients and oxygen with the needs of the fetus in that prevailing environment. In particular, placental structure (e.g. vascularity, surface area, blood flow, diffusion distance) and transport capacity (e.g. nutrient transporter levels and activity) respond to suboptimal gestational environments, namely malnutrition, obesity, hypoxia and maternal ageing. Mechanisms mediating developmentally and environmentally induced homeostatic responses of the placenta that help support normal fetal growth include imprinted genes, signalling pathways, subcellular constituents and fetal sexomes. Identification of these placental strategies may inform the development of therapies for complicated human pregnancies and advance understanding of the pathways underlying poor fetal outcomes and their consequences for health and disease risk.
... Maternal lifestyle habits, such as the type and quantity of food at preconception [58], gestation [59], and lactation [60], may influence critical periods of fetal/infant development, contributing to future offspring complications [58][59][60][61]. Maternal malnutrition is associated with an increased risk of obesity, T2D, and CVD in young and adult offspring [62][63][64]. ...
... Maternal lifestyle habits, such as the type and quantity of food at preconception [58], gestation [59], and lactation [60], may influence critical periods of fetal/infant development, contributing to future offspring complications [58][59][60][61]. Maternal malnutrition is associated with an increased risk of obesity, T2D, and CVD in young and adult offspring [62][63][64]. ...
Type 2 diabetes (T2D) has increased worldwide at an alarming rate. Metabolic syndrome (MetS) is a major risk factor for T2D development. One of the main reasons for the abrupt rise in MetS incidence, besides a sedentary lifestyle, is the westernized diet consumption, with high content of industrialized foods, rich in added dietary sugars (DS), mainly sucrose and fructose. It has been suggested that a higher intake of DS could impair metabolic function, inducing MetS, and predisposing to T2D. However, it remains poorly explored how excessive DS intake modulates mitochondrial function, a key player in metabolism. This review explores the relationship between increased consumption of DS and mitochondrial dysfunction associated with T2D development, pointing to a contribution of the diet-induced accumulation of advanced glycation end-products (AGEs), with brief insights on the impact of maternal high-sugar diet and AGEs consumption during gestation on offspring increased risk of developing T2D later in life, contributing to perpetuate T2D propagation.
