Placental mTOR Signaling and Sexual Dimorphism in Metabolic Health across the Lifespan of Offspring

Robust evidence of fetal programming of adult disease has surfaced in the last several decades. Human and preclinical investigations of intrauterine insults report perturbations in placental nutrient sensing by the mechanistic target of rapamycin (mTOR). This review focuses on pregnancy complications associated with placental mTOR regulation, such as fetal growth restriction (FGR), fetal overgrowth, gestational diabetes mellitus (GDM), polycystic ovarian syndrome (PCOS), maternal nutrient restriction (MNR), preeclampsia (PE), maternal smoking, and related effects on offspring birthweight. The link between mTOR-associated birthweight outcomes and offspring metabolic health trajectory with a focus on sexual dimorphism are discussed. Both human physiology and animal models are summarized to facilitate in depth understanding. GDM, PCOS and fetal overgrowth are associated with increased placental mTOR, whereas FGR, MNR and maternal smoking are linked to decreased placental mTOR activity. Generally, birth weight is reduced in complications with decreased mTOR (i.e., FGR, MNR, maternal smoking) and higher with increased mTOR (GDM, PCOS). Offspring display obesity or a higher body mass index in childhood and adulthood, impaired glucose and insulin tolerance in adulthood, and deficiencies in pancreatic beta-cell mass and function compared to offspring from uncomplicated pregnancies. Defining causal players in the fetal programming of offspring metabolic health across the lifespan will aid in stopping the vicious cycle of obesity and type II diabetes

Epigenetic mechanisms of anti-cancer effects of dietary stilbenoids

Epigenetics refers to control of gene expression without changes to the underlying DNA sequence. DNA methylation, a dynamic epigenetic modification responsive to environmental factors, underlies genomic instability, silencing of tumor suppressor genes (TSGs), and activation of genes driving cancer development. Reversing DNA methylation patterns established during carcinogenesis constitutes a promising anti-cancer strategy. Interestingly, certain dietary polyphenols, such as stilbenoids abundantly found in grapes and blueberries, have been shown to exert anti-cancer effects through epigenetic gene regulation. The overarching objective of my research is to understand epigenetic mechanisms of stilbenoids’ anti-cancer effects. We hypothesize that dietary stilbenoids, resveratrol (RSV) and pterostilbene (PTS), modulate DNA methylation patterns and thereby gene transcription via modifying expression and activity of epigenetic enzymes such as DNA methyltransferases (DNMTs) and transcriptional machinery such as transcription factors (TFs). Stilbenoid-induced changes in DNA methylation and transcriptional machinery could, in turn, lead to reactivation of methylation-silenced TSGs and downregulation of epigenetically-activated oncogenes leading to reduced cancer development. Upon treatment with RSV (15 μM, 9 days), DNA methylation levels in MCF10CA1a breast cancer cells were altered as assessed by genome-wide DNA methylation analysis. Hypermethylated CpG sites corresponded to genes predominantly associated with oncogenic functions, whereas hypomethylated sites were located in genes with potential tumor suppressor roles. Changes in methylation and expression of candidate oncogenes and TSGs were examined using pyrosequencing and qPCR, respectively, upon treatment with RSV or PTS. Further, chromatin immunoprecipitation (ChIP) sequencing assessed DNA binding events, including occupancy of DNMTs and TFs at stilbenoid-mediated differentially methylated sites. Specific putative roles for de novo DNMTs in mediating changes in DNA methylation patterns upon exposure to stilbenoids were established. Based on our findings in cell lines, we turned to an in vivo model of methyl donor deficiency to assess the contribution of methyl donors, another important factor for maintaining normal DNA methylation patterns, to carcinogenesis. Collectively, these findings provide evidence that dietary stilbenoids may exert their anti-cancer effects, at least partially, by impacting DNA methylation machinery, and as a result, this line of evidence has potential to be used to develop novel anti-cancer approaches.Land and Food Systems, Faculty ofGraduat

<strong>Sex differences in pancreatic beta cell physiology and glucose homeostasis in C57BL/6J mice </strong>

Supplemental Data for manuscript entitled,    Sex differences in pancreatic beta cell physiology and glucose homeostasis in C57BL/6J mice, Jo et al, JES, 2023</p

Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams

In pregnancies complicated by maternal obesity and gestational diabetes mellitus, there is strong evidence to suggest that the insulin signaling pathway in the placenta may be impaired. This may have potential effects on the programming of the metabolic health in the offspring; however, a direct link between the placental insulin signaling pathway and the offspring health remains unknown. Here, we aimed to understand whether specific placental loss of the insulin receptor (InsR) has a lasting effect on the offspring health in mice. Obesity and glucose homeostasis were assessed in the adult mouse offspring on a normal chow diet (NCD) followed by a high-fat diet (HFD) challenge. Compared to their littermate controls, InsR KOplacenta offspring were born with normal body weight and pancreatic &beta;-cell mass. Adult InsR KOplacenta mice exhibited normal glucose homeostasis on an NCD. Interestingly, under a HFD challenge, adult male InsR KOplacenta offspring demonstrated lower body weight and a mildly improved glucose homeostasis associated with parity. Together, our data show that placenta-specific insulin receptor deletion does not adversely affect offspring glucose homeostasis during adulthood. Rather, there may potentially be a mild and transient protective effect in the mouse offspring of multiparous dams under the condition of a diet-induced obesogenic challenge

JC1

Contains all JC-1 assay (mitochondrial membrane potential) dat

respirometry

Contains all raw oxygen consumption data

Reduction in O-GlcNAcylation Mitigates the Severity of Inflammatory Response in Cerulein-Induced Acute Pancreatitis in a Mouse Model

Acute pancreatitis (AP) involves premature trypsinogen activation, which mediates a cascade of pro-inflammatory signaling that causes early stages of pancreatic injury. Activation of the transcription factor &kappa;B (NF-&kappa;B) and secretion of pro-inflammatory mediators are major events in AP. O-GlcNAc transferase (OGT), a stress-sensitive enzyme, was recently implicated to regulate NF-&kappa;B activation and inflammation in AP in vitro. This study aims to determine whether a pancreas-specific transgenic reduction in OGT in a mouse model affects the severity of AP in vivo. Mice with reduced pancreatic OGT (OGTPanc+/&minus;) at 8 weeks of age were randomized to cerulein, which induces pancreatitis, or saline injections. AP was confirmed by elevated amylase levels and on histological analysis. The histological scoring demonstrated that OGTPanc+/&minus; mice had decreased severity of AP. Additionally, serum lipase, LDH, and TNF-&alpha; in OGTPanc+/&minus; did not significantly increase in response to cerulein treatment as compared to controls, suggesting attenuated AP induction in this model. Our study reveals the effect of reducing pancreatic OGT levels on the severity of pancreatitis, warranting further investigation on the role of OGT in the pathology of AP

Data from: Genetic variation for mitochondrial function in the New Zealand freshwater snail Potamopyrgus antipodarum

The proteins responsible for mitochondrial function are encoded by two different genomes with distinct inheritance regimes, rendering rigorous inference of genotype–phenotype connections intractable for all but a few model systems. Asexual organisms provide a powerful means to address these challenges because offspring produced without recombination inherit both nuclear and mitochondrial genomes from a single parent. As such, these offspring inherit mitonuclear genotypes that are identical to the mitonuclear genotypes of their parents and siblings and different from those of other asexual lineages. Here, we compared mitochondrial function across distinct asexual lineages of Potamopyrgus antipodarum, a New Zealand freshwater snail model for understanding the evolutionary consequences of asexuality. Our analyses revealed substantial phenotypic variation across asexual lineages at three levels of biological organization: mitogenomic, organellar, and organismal. These data demonstrate that different asexual lineages have different mitochondrial function phenotypes, likely reflecting heritable variation (that is, the raw material for evolution) for mitochondrial function in P. antipodarum. The discovery of this variation combined with the methods developed here sets the stage to use P. antipodarum to study central evolutionary questions involving mitochondrial function, including whether mitochondrial mutation accumulation influences the maintenance of sexual reproduction in natural populations