Biology subjects

Redd, J. R.

Publications and source records attributed to Redd, J. R..

8 recordsLinked to original sources

bioRxiv2024

Accelerated amyloid deposition in SARS-CoV-2 infected mouse models of Alzheimer's disease

Familial Alzheimers disease (AD) involving known AD causing genes accounts for a small fraction of cases, the vast majority are sporadic. Neuroinflammation, secondary to viral infection, has been suggested as an initiating or accelerating factor. In this work we tested the hypothesis that SARS-CoV-2 (SCV2) viral infection accelerates the development of AD pathology in mouse models of AD. We profiled transcriptomic changes using transgenic APP/PSEN1 and P301S mouse models that develop AD pathology and k18hACE2 mice that express the humanized ACE2 receptor used by SCV2 to enter cells. This study identified the interferon and chemokine responses constituting key shared pathways between SCV2 infection and the development of AD pathology. Two transgenic mouse models of AD: APP/PSEN1 (develops amyloid pathology) and 3xTg AD (develops both amyloid and tau pathology) were crossed with k18-hACE2 mice to generate hybrid hACE2-3xTg and hACE2-APP/PSEN1 mice. Neuroinflammation and amyloid deposition in the brain of infected mice were imaged in vivo using molecular MRI (mMRI) probes and confirmed postmortem by histopathology. Results show that 11-14-month-old SCV2 infected hACE2-3xTg mice exhibit neuroinflammation 10 days post infection and 4-5-month-old hACE2-APP/PS1 hybrid mice develop amyloid deposits, while age-matched uninfected mice exhibit neither phenotype. This suggests that SCV2 infection could induce or accelerate AD when risk factors are present.

neuroscience↗

bioRxiv2024

Reduced beta-hydroxybutyrate disposal after ketogenic diet feeding in mice

The ketogenic diet (KD) has garnered considerable attention due to its potential benefits in weight loss, health improvement, and performance enhancement. However, the phenotypic responses to KD vary widely between individuals. Skeletal muscle is a major contributor to ketone body (KB) catabolism, however, the regulation of ketolysis is not well understood. In this study, we evaluated how mTORC1 activation and a ketogenic diet modify ketone body disposal in muscle Tsc1 knockout (KO) mice, inbred A/J mice, and Diversity Outbred (DO) mice. Muscle Tsc1 KO mice demonstrated enhanced ketone body clearance. Contrary to expectations, KD feeding in A/J mice did not improve KB disposal, and in most strains disposal was reduced. Transcriptional analysis revealed reduced expression of important ketolytic genes in KD-fed A/J mice, suggesting impaired KB catabolism. Diversity Outbred (DO) mice displayed variable responses to KD, with most mice showing worsened KB disposal. Exploratory analysis on these data suggest potential correlations between KB disposal and cholesterol levels as well as weight gain on a KD. Our findings suggest that ketone body disposal may be regulated by both nutritional and genetic factors and these relationships may help explain interindividual variability in responses to ketogenic diets.

physiology↗

bioRxiv2024

GDF15 knockout does not substantially impact perinatal body weight or neonatal outcomes in mice

Growth differentiation factor-15 (GDF15) increases in circulation during pregnancy and has been implicated in food intake, weight loss, complications of pregnancy, and metabolic illness. We used a Gdf15 knockout mouse model (Gdf15-/- ) to assess the role of GDF15 in body weight regulation and food intake during pregnancy. We found that Gdf15-/- dams consumed a similar amount of food and gained comparable weight during the course of pregnancy compared to Gdf15+/+ dams. Insulin sensitivity on gestational day 16.5 was also similar between genotypes. In the postnatal period, litter size, and survival rates were similar between genotypes. There was a modest reduction in birth weight of Gdf15-/- pups, but this difference was no longer evident postnatal day 3.5 to 14.5. We observed no detectable differences in milk volume production or milk fat percentage. These data suggest that GDF15 is dispensable for changes in food intake, and body weight as well as insulin sensitivity during pregnancy in a mouse model.

physiology↗

bioRxiv2022

Gestational Early-Time Restricted Feeding Results in Sex-Specific Glucose Intolerance in Adult Male Mice

The timing of food intake is a novel dietary component that can impact health. Time-restricted feeding (TRF), a form of intermittent fasting, manipulates food timing. During pregnancy, one may experience disruptions to food intake for diverse reasons (e.g. nausea and vomiting of pregnancy, food insecurity, desire to manage gestational weight gain, disordered eating behaviors, changes in taste and food preferences, etc) and therefore may experience periods of intentional or unintentional fasting similar to TRF protocols. Because interest in TRF is gaining popularity and feeding may be interrupted in those who are pregnant, it is important to understand the long-term effects of TRF during pregnancy on the resultant offspring. Using a mouse model, we tested the effects of gestational exposure to early TRF (eTRF) over the life course of both male and female offspring. Offspring body composition was similar between experimental groups in both males and females from weaning (day 21) to adulthood (day 70), with minor increases in food intake in eTRF females and improved glucose tolerance in males. After 10 weeks of high fat, high sucrose diet feeding, male eTRF offspring were more sensitive to insulin but developed glucose intolerance with impaired insulin secretion. As such, gestational eTRF causes sex-specific deleterious effects on glucose homeostasis after chronic high fat, high sucrose diet feeding in male offspring. Further studies are needed to determine the effect gestational eTRF has on the male pancreas as well as to elucidate the mechanisms that protect females from this metabolic dysfunction.

physiology↗

bioRxiv2021

Activation of Adipocyte mTORC1 Increases Milk Lipids in a Mouse Model of Lactation

Human milk is the recommended nutrient source for newborns. The mammary gland comprises multiple cell types including epithelial cells and adipocytes. The contributions of mammary adipocytes to breast milk composition and the intersections between mammary nutrient sensing and milk lipids are not fully understood. A major nutrient sensor in most tissues is the mechanistic target of rapamycin 1 (mTORC1). To assess the role of excess nutrient sensing on mammary gland structure, function, milk composition, and offspring weights, we used an Adiponectin-Cre driven Tsc1 knockout model of adipocyte mTORC1 hyperactivation. Our results show that the knockout dams have higher milk fat contributing to higher milk caloric density and heavier offspring weight during lactation. Additionally, milk of knockout dams displayed a lower percentage of saturated fatty acids, higher percentage of monounsaturated fatty acids, and a lower milk {omega}6: {omega}3 ratio driven by increases in docosahexaenoic acid (DHA). Mammary gland gene expression analyses identified changes in eicosanoid metabolism, adaptive immune function, and contractile gene expression. Together, these results suggest a novel role of adipocyte mTORC1 in mammary gland function and morphology, milk composition, and offspring growth.

physiology↗

bioRxiv2020

Obesity promotes glucocorticoid-dependent muscle atrophy in male C57BL/6J mice.

Glucocorticoids promote muscle atrophy by inducing a class of proteins called atrogenes, resulting in reductions in muscle size and strength. In this work, we evaluated whether a mouse model with pre-existing diet-induced obesity had altered glucocorticoid responsiveness. We observed that all animals treated with the synthetic glucocorticoid dexamethasone had reduced strength, but that obesity exacerbated this effect. These changes were concordant with more pronounced reductions in muscle size, particularly in Type II muscle fibers, and potentiated induction of atrogene expression in the obese mice relative to lean mice. Furthermore, we show that the reductions in lean mass do not fully account for the dexamethasone-induced insulin resistance observed in these mice. Together these data suggest that obesity potentiates glucocorticoid-induced muscle atrophy.

physiology↗

bioRxiv2019

Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

The mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and age-associated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet-and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal muscle-specific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca2+ through SERCA2. Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan. These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.

physiology↗

bioRxiv2017

Glucocorticoid-Induced Metabolic Disturbances are Exacerbated in Obesity

Obesity and chronically elevated glucocorticoids result in similar co-morbidities, but the effect of a combination of these ailments on metabolic outcomes is unclear. Measures of glucose homeostasis and markers of hepatic lipid accumulation were assessed to determine whether obesity exaggerated the effects of dexamethasone-induced metabolic disturbances. The combination of obesity and glucocorticoids resulted in hepatic steatosis and synergistic impairments in insulin sensitivity and this was matched with synergistic elevations in markers of lipolysis. These findings suggest lipolysis may be a key player in glucocorticoid-induced insulin resistance and fatty liver in people with obesity.

physiology↗