Biology subjects

McCurdy, C. E.

Publications and source records attributed to McCurdy, C. E..

4 recordsLinked to original sources

bioRxiv2026

Maternal Western-style Diet Promotes Immune Tolerance and Liver Sinusoidal Endothelial Cell Dysfunction in Nonhuman Primate Juvenile Offspring Liver

Maternal Western-style diet (mWSD) consumption during pregnancy and lactation is associated with developmental programming of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring. To understand the roles of immune and endothelial cells, we used single-cell RNA-sequencing of liver non-parenchymal cells from 3-year-old juvenile nonhuman primates exposed to mWSD during their gestation through weaning, followed by control diet consumption after weaning. We identified unique clusters of macrophages in mWSD-exposed juvenile livers with non-reparative, pro-fibrotic phenotypes characterized by predicted inactivation of NF-{kappa}B, decreased oxidative phosphorylation, and gene expression facilitating hepatic stellate cell-macrophage interactions. Kupffer cell and dendritic cell (DC) numbers were decreased by mWSD exposure, with inactivation of inflammatory and antigen presentation pathways in DCs, supporting DC immaturity. B cells increased in mWSD-exposed offspring, with RNA showing reduced inflammation and impaired differentiation, while T cells had RNA profiles consistent with apoptosis and reduced inflammatory function. mWSD exposure increased clusters of liver sinusoidal endothelial cells (LSECs), with activation of inflammation and proliferation pathways but decreased immune cell communication. Immunocytochemistry and RNAscope identified increased association of LSECs and immune cells in periportal regions. In summary, mWSD exposure during gestation and lactation selectively modulated LSEC-immune cell interactions consistent with immune tolerant B and T cells and fibrogenic pathways together with decreased pro-resolving macrophages in juvenile offspring. We conclude that mWSD exposure establishes an immune-tolerant environment in offspring liver, marked by a durable, pro-fibrotic microenvironment that resists postnatal dietary correction.

immunology↗

bioRxiv2025

APOE4 genotype negates the benefits of 17β-estradiol on cerebrovascular endothelial and mitochondrial function

BackgroundPostmenopausal females who carry an APOE{varepsilon}4 allele are at higher risk of late-onset Alzheimers Disease compared to age-matched APOE{varepsilon}4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive, and metabolic impairments. While estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, their cerebrovascular effects are less understood. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen on cerebrovascular endothelial and mitochondrial function. MethodsYoung female homozygous APOE{varepsilon}3 and APOE{varepsilon}4 mice (n=19-20/group; ~6 months old) fed a high-fat diet were ovariectomized (OVX), OVX and supplemented with 17{beta}-estradiol, or left intact. ResultsIn APOE{varepsilon}3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilation, which was rescued by 17{beta}-estradiol. However, in APOE{varepsilon}4 mice, there was no effect of OVX or 17{beta}-estradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17{beta}-estradiol treatment in APOE{varepsilon}3 mice, but there was no impact of OVX or 17{beta}-estradiol in the APOE{varepsilon}4 mice. In cerebral arteries and arterioles, mitochondrial complexes I and I+II respiration were lower in APOE{varepsilon}4 mice compared with APOE{varepsilon}3 mice. 17{beta}-estradiol led to higher mitochondrial complex I respiration in APOE{varepsilon}3 but not APOE{varepsilon}4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes, and pro-inflammatory factors. In contrast to other outcomes, we found that 17{beta}-estradiol treatment was associated with lower cerebral artery stiffness in APOE{varepsilon}4 but not APOE{varepsilon}3 mice. ConclusionsOverall, these results indicate that the APOE genotype modulates the impact of estrogen on the cerebral vasculature. We found that 17{beta}-estradiol enhances cerebrovascular endothelial and mitochondrial function in APOE{varepsilon}3 mice but not in APOE{varepsilon}4 mice. The results suggest that 17{beta}-estradiol supplementation has more cerebrovascular benefit for APOE{varepsilon}4 non-carriers. Novelty & SignificanceO_ST_ABSWhat is known?C_ST_ABSO_LIFemales have twice the risk of Alzheimers disease compared with males, and the APOE4 genetic variant is associated with a greater risk for Alzheimers disease compared with the APOE3 variant. C_LIO_LIThe risk for Alzheimers disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. C_LIO_LIThere are highly inconsistent results among past studies examining the interaction of APOE genotype and estrogens on cognitive function and other brain outcomes. C_LI What new information does this article contribute?Vascular outcomes were not measured in previous studies examining the interaction between APOE genotype and estrogens. As such, we aimed to determine the impact of APOE4 genotype on the cerebrovascular response to estradiol. We found that estradiol improved cerebral artery endothelial function and mitochondrial respiration in APOE3 mice following ovariectomy. In contrast, APOE4 mice were refractory to the beneficial effects of estradiol on cerebrovascular endothelial and mitochondrial function. The broader implication of this research is that APOE genotype may be a consideration when prescribing hormone replacement therapy to menopausal females due to the impact on vascular outcomes.

physiology↗

bioRxiv2024

Maternal Western-style diet programs skeletal muscle gene expression in lean adolescent Japanese macaque offspring

Early-life exposure to maternal obesity or a maternal calorically dense Western-style diet (WSD) is strongly associated with a greater risk of metabolic diseases in offspring, most notably insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). Prior studies in our well-characterized Japanese macaque model demonstrated that offspring of dams fed a WSD, even when weaned onto a control (CTR) diet, had reductions in skeletal muscle mitochondrial metabolism and increased skeletal muscle insulin resistance compared to offspring of dams on CTR diet. In the current study, we employed a nested design to test for differences in gene expression in skeletal muscle from lean 3-year-old adolescent offspring from dams fed a maternal WSD in both the presence and absence of maternal obesity or lean dams fed a CTR diet. We included offspring weaned to both a WSD or CTR diet to further account for differences in response to post-weaning diet and interaction effects between diets. Overall, we found that a maternal WSD fed to dams during pregnancy and lactation was the principal driver of differential gene expression (DEG) in offspring muscle at this time point. We identified key gene pathways important in insulin signaling including PI3K-Akt and MAP-kinase, regulation of muscle regeneration, and transcription-translation feedback loops, in both male and female offspring. Muscle DEG showed no measurable difference between offspring of obese dams on WSD compared to those of lean dams fed WSD. A post-weaning WSD effected offspring transcription only in individuals from the maternal CTR diet group but not in maternal WSD group. Collectively, we identify that maternal diet composition has a significant and lasting impact on offspring muscle transcriptome and influences later transcriptional response to WSD in muscle, which may underlie the increased metabolic disease risk in offspring.

physiology↗

bioRxiv2019

Maternal Obesity and Western-style Diet Impair Fetal and Juvenile Offspring Skeletal Muscle Insulin-Stimulated Glucose Transport in Nonhuman Primates

Infants born to mothers with obesity have a greater risk for childhood obesity and metabolic diseases; however, the underlying biological mechanisms remain poorly understood. We used a nonhuman primate model to investigate whether maternal obesity combined with a western-style diet (WSD) impairs offspring muscle insulin action. Briefly, adult females were fed a control (CON) or WSD prior to and during pregnancy and lactation. Offspring were weaned to a CON or WSD. Muscle glucose uptake and insulin signaling were measured ex vivo in fetal and juvenile offspring. In vivo signaling was evaluated before and after an intravenous insulin bolus just prior to weaning. We find that fetal muscle exposed to maternal WSD had reduced insulin-stimulated glucose uptake and impaired insulin signaling. In juvenile offspring, insulin-stimulated glucose uptake was similarly reduced by both maternal and post-weaning WSD. Analysis of insulin signaling activation revealed distinct changes between fetal and post-weaning WSD exposure. We conclude that maternal WSD leads to a persistent decrease in insulin-stimulated glucose uptake in juvenile offspring even in the absence of increased offspring adiposity or markers of systemic insulin resistance. Switching offspring to a healthy diet did not ameliorate the effects of maternal WSD suggesting earlier interventions may be necessary.

physiology↗