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.

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.

Hippocampus Glutathione S Reductase Potentially Confers Genetic Resilience to Cognitive Decline in the AD-BXD Mouse Population.

Alzheimer's disease (AD) is a prevalent and costly age-related dementia. Heritable factors account for 58-79% of variation in late-onset AD, but substantial variation remains in age-of- onset, disease severity, and whether those with high-risk genotypes acquire AD. To emulate the diversity of human populations, we utilized the AD-BXD mouse panel. This genetically diverse resource combines AD genotypes with multiple BXD strains to discover new genetic drivers of AD resilience. Comparing AD-BXD carriers to noncarrier littermates, we computed a novel quantitative metric for resilience to cognitive decline in the AD-BXDs. Our quantitative AD resilience trait was heritable and genetic mapping identified a locus on chr8 associated with resilience to AD mutations that resulted in amyloid brain pathology. Using a hippocampus proteomics dataset, we nominated the mitochondrial glutathione S reductase protein (GR or GSHR) as a resilience factor, finding that the DBA/2J genotype was associated with substantially higher GR abundance. By mapping protein QTLs (pQTLs), we identified synaptic organization and mitochondrial proteins coregulated in trans with a cis-pQTL for GR. We found four coexpression modules correlated with the quantitative resilience score in aged 5XFAD mice using paracliques, which were related to cell structure, protein folding, and postsynaptic densities. Finally, we found significant positive associations between human GSR transcript abundance in the brain and better outcomes on AD-related cognitive and pathology traits in the Religious Orders Study/Memory and Aging project (ROSMAP). Taken together, these data support a framework for resilience in which neuronal antioxidant pathway activity provides for stability of synapses within the hippocampus.

Cross-sectional association between blood cholesterol and calcium levels in genetically diverse strains of mice.

Genetically diverse outbred mice allow for the study of genetic variation in the context of high dietary and environmental control. Using a machine learning approach, we investigated clinical and morphometric factors that associate with serum cholesterol levels in 840 genetically unique Diversity Outbred mice of both sexes (n = 417 male and 423 female), and on both a control chow (% kcals in diet: protein 22%, carbohydrate 62%, fat 16%, no cholesterol) and high fat high sucrose (% kcals in diet: protein 15%, carbohydrate 41%, fat 45%, 0.05% cholesterol). We find expected elevations of cholesterol in male mice, as well as in mice with elevated serum triglycerides and/or fed a high fat high sucrose diet. The third strongest predictor was serum calcium which correlated with serum cholesterol across both diets and sexes (r = 0.39-0.48) in both Diversity Outbred (P = 3.0 × 10-43 ) and BXD (P = 0.005) mice. This is in-line with several human cohort studies which show associations between calcium and cholesterol, and calcium as an independent predictor of cardiovascular events.

The Influence of Maternal High Fat Diet During Lactation on Offspring Hematopoietic Priming.

Obesity and metabolic diseases are rising among women of reproductive age, increasing offspring metabolic risk. Maternal nutritional interventions during lactation present an opportunity to modify offspring outcomes. We previously demonstrated in mice that adult male offspring have metabolic impairments and increased adipose tissue macrophages (ATM) when dams are fed high fat diet (HFD) during the postnatal lactation window (HFD PN). We sought to understand the effect of HFD during lactation on early-life inflammation. HFD PN offspring were evaluated at postnatal day 16 to 19 for tissue weight and gene expression. Profiling of adipose tissue and bone marrow immune cells was conducted through lipidomics, in vitro myeloid colony forming unit assays, and flow cytometry. HFD PN mice had more visceral gonadal white adipose tissue (GWAT) and subcutaneous fat. Adipose tissue RNA sequencing demonstrated enrichment of inflammation, chemotaxis, and fatty acid metabolism and concordant changes in GWAT lipidomics. Bone marrow (BM) of both HFD PN male and female offspring had increased monocytes (CD45+Ly6G-CD11b+CD115+) and B cells (CD45+Ly6G-CD11b-CD19+). Similarly, serum from HFD PN offspring enhanced in vitro BM myeloid colonies in a toll-like receptor 4-dependent manner. We identified that male HFD PN offspring had increased GWAT pro-inflammatory CD11c+ ATMs (CD45+CD64+). Maternal exposure to HFD alters milk lipids enhancing adiposity and myeloid inflammation even in early life. Future studies are needed to understand the mechanisms driving this pro-inflammatory state of both BM and ATMs, the causes of the sexually dimorphic phenotypes, and the feasibility of intervening in this window to improve metabolic health.

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 impacts health. Time-restricted feeding (TRF), a form of intermittent fasting, manipulates food timing. The timing of eating may be an important factor to consider during critical periods, such as pregnancy. Nutrition during pregnancy, too, can have a lasting impact on offspring health. The timing of food intake has not been thoroughly investigated in models of pregnancy, despite evidence that interest in the practice exists. Therefore, using a mouse model, we tested body composition and glycemic health of gestational early TRF (eTRF) in male and female offspring from weaning to adulthood on a chow diet and after a high-fat, high-sucrose (HFHS) diet challenge. Body composition was similar between groups in both sexes from weaning to adulthood, with minor increases in food intake in eTRF females and slightly improved glucose tolerance in males while on a chow diet. However, after 10 weeks of HFHS, male eTRF offspring developed glucose intolerance. Further studies should assess the susceptibility of males, and apparent resilience of females, to gestational eTRF and assess mechanisms underlying these changes in adult males.

Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction.

BACKGROUND: As critical care practice evolves, the sepsis survivor population continues to expand, often with lingering inflammation in many organs, including the liver. Given the concurrently increasing population of patients with NAFLD, in this study, we aimed to understand the long-term effect of sepsis on pre-existing NAFLD and hyperglycemia. METHODS: Male mice were randomized to a high-fat diet or a control diet (CD). After 24 weeks on diet, mice were inoculated with Klebsiella pneumoniae (Kpa). Serial glucose tolerance tests, and insulin and pyruvate challenge tests were performed 1 week before infection and at 2 and 6 weeks after infection. Whole tissue RNA sequencing and histological evaluation of the liver were performed. To test whether persistent inflammation could be reproduced in other abnormal liver environments, mice were also challenged with Kpa after exposure to a methionine-choline-deficient high-fat diet. Finally, a retrospective cohort of 65,139 patients was analyzed to evaluate whether obesity was associated with liver injury after sepsis. RESULTS: After Kpa inoculation, high-fat diet mice had normalized fasting blood glucose without a change in insulin sensitivity but with a notable decrease in pyruvate utilization. Liver examination revealed focal macrophage collections and a unique inflammatory gene signature on RNA analysis. In the clinical cohort, preobesity, and class 1 and class 2 obesity were associated with increased odds of elevated aminotransferase levels 1-2 years after sepsis. CONCLUSIONS: The combination of diet-induced obesity and pneumosepsis survival in a murine model resulted in unique changes in gluconeogenesis and liver inflammation, consistent with the progression of benign steatosis to steatohepatitis. In a cohort study, obese patients had an increased risk of elevated aminotransferase levels 1-2 years following sepsis.

Cross-sectional association between blood cholesterol and calcium levels in genetically diverse strains of mice.

Genetically diverse outbred mice allow for the study of genetic variation in the context of high dietary and environmental control. Using a machine learning approach we investigated clinical and morphometric factors that associate with serum cholesterol levels in 840 genetically unique mice of both sexes, and on both a control chow and high fat high sucrose diet. We find expected elevations of cholesterol in male mice, those with elevated serum triglycerides and/or fed a high fat high sucrose diet. The third strongest predictor was serum calcium which correlated with serum cholesterol across both diets and sexes (r=0.39-0.48). This is in-line with several human cohort studies which show associations between calcium and cholesterol, and calcium as an independent predictor of cardiovascular events.

Sexually concordant and dimorphic transcriptional responses to maternal trichloroethylene and/or N-acetyl cysteine exposure in Wistar rat placental tissue.

Numerous Superfund sites are contaminated with the volatile organic chemical trichloroethylene (TCE). In women, exposure to TCE in pregnancy is associated with reduced birth weight. Our previous study reported that TCE exposure in pregnant rats decreased fetal weight and elevated oxidative stress biomarkers in placentae, suggesting placental injury as a potential mechanism of TCE-induced adverse birth outcomes. In this study, we investigated if co-exposure with the antioxidant N-acetylcysteine (NAC) attenuates TCE exposure effects on RNA expression. Timed-pregnant Wistar rats were exposed orally to 480 mg TCE/kg/day on gestation days 6-16. Exposure of 200 mg NAC/kg/day alone or as a pre/co-exposure with TCE occurred on gestation days 5-16 to stimulate antioxidant genes prior to TCE exposure. Tissue was collected on gestation day 16. In male and female placentae, we evaluated TCE- and/or NAC-induced changes to gene expression and pathway enrichment analyses using false discovery rate (FDR) and fold-change criteria. In female placentae, exposure to TCE caused significant differential expression 129 genes while the TCE+NAC altered 125 genes, compared with controls (FDR< 0.05 + fold-change >1). In contrast, in male placentae TCE exposure differentially expressed 9 genes and TCE+NAC differentially expressed 35 genes, compared with controls (FDR< 0.05 + fold-change >1). NAC alone did not significantly alter gene expression in either sex. Differentially expressed genes observed with TCE exposure were enriched in mitochondrial biogenesis and oxidative phosphorylation pathways in females whereas immune system pathways and endoplasmic reticulum stress pathways were differentially expressed in both sexes (FDR<0.05). TCE treatment was differentially enriched for genes regulated by the transcription factors ATF6 (both sexes) and ATF4 (males only), indicating a cellular condition triggered by misfolded proteins during endoplasmic reticulum stress. This study demonstrates novel genes and pathways involved in TCE-induced placental injury and showed antioxidant co-treatment largely did not attenuate TCE exposure effects.

Chronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue.

Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.

Associations of bacterial enteropathogens with systemic inflammation, iron deficiency, and anemia in preschool-age children in southern Ghana.

Anemia remains a pervasive public health problem among preschool-age children in Ghana. Recent analyses have found that anemia in Ghanaian children, particularly in Southern regions, is largely attributable to infectious causes, rather than nutritional factors. Infections with enteropathogens can reduce iron absorption and increase systemic inflammation, but few studies have examined direct links between enteropathogens and anemia. This study investigated associations between detection of individual bacterial enteropathogens and systemic inflammation, iron deficiency, and anemia among 6- to 59-month-old children in Greater Accra, Ghana. Serum samples were analyzed from a cross-sectional sample of 262 children for concentrations of hemoglobin (Hb), biomarkers of systemic inflammation [C-reactive protein (CRP) and α-1-acid glycoprotein (AGP)], and biomarkers of iron status [serum ferritin (SF) and serum transferrin receptor (sTfR)]. Stool samples were analyzed for ten bacterial enteropathogens using qPCR. We estimated associations between presence of each enteropathogen and elevated systemic inflammation (CRP > 5 mg/L and AGP > 1 g/L), iron deficiency (SF < 12 µg/L and sTfR > 8.3 mg/L) and anemia (Hb < 110 g/L). Enteropathogens were detected in 87% of children's stool despite a low prevalence of diarrhea (6.5%). Almost half (46%) of children had anemia while one-quarter (24%) had iron deficiency (low SF). Despite finding no associations with illness symptoms, Campylobacter jejuni/coli detection was strongly associated with elevated CRP [Odds Ratio (95% CI): 3.49 (1.45, 8.41)] and elevated AGP [4.27 (1.85, 9.84)]. Of the pathogens examined, only enteroinvasive Escherichia coli/Shigella spp. (EIEC/Shigella) was associated with iron deficiency, and enteroaggregative Escherichia coli (EAEC) [1.69 (1.01, 2.84)] and EIEC/Shigella [2.34 (1.15, 4.76)] were associated with anemia. These results suggest that certain enteroinvasive pathogenic bacteria may contribute to child anemia. Reducing exposure to enteropathogens through improved water, sanitation, and hygiene practices may help reduce the burden of anemia in young Ghanaian children.

Short Term Changes in Dietary Fat Content and Metformin Treatment During Lactation Impact Milk Composition and Mammary Gland Morphology.

Maternal health and diet can have important consequences for offspring nutrition and metabolic health. During lactation, signals are communicated from the mother to the infant through milk via macronutrients, hormones, and bioactive molecules. In this study we designed experiments to probe the mother-milk-infant triad in the condition of normal maternal health and upon exposure to high fat diet (HFD) with or without concurrent metformin exposure. We examined maternal characteristics, milk composition and offspring metabolic parameters on postnatal day 16, prior to offspring weaning. We found that lactational HFD increased maternal adipose tissue weight, mammary gland adipocyte size, and altered milk lipid composition causing a higher amount of omega-6 (n6) long chain fatty acids and lower omega-3 (n3). Offspring of HFD dams were heavier with more body fat during suckling. Metformin (Met) exposure decreased maternal blood glucose and several milk amino acids. Offspring of met dams were smaller during suckling. Gene expression in the lactating mammary glands was impacted to a greater extent by metformin than HFD, but both metformin and HFD altered genes related to muscle contraction, indicating that these genes may be more susceptible to lactational stressors. Our study demonstrates the impact of common maternal exposures during lactation on milk composition, mammary gland function and offspring growth with metformin having little capacity to rescue the offspring from the effects of a maternal HFD during lactation.

Diet-induced obesity in mice impairs host defense against Klebsiella pneumonia in vivo and glucose transport and bactericidal functions in neutrophils in vitro.

Obesity impairs host defense against Klebsiella pneumoniae, but responsible mechanisms are incompletely understood. To determine the impact of diet-induced obesity on pulmonary host defense against K. pneumoniae, we fed 6-wk-old male C57BL/6j mice a normal diet (ND) or high-fat diet (HFD) (13% vs. 60% fat, respectively) for 16 wk. Mice were intratracheally infected with Klebsiella, assayed at 24 or 48 h for bacterial colony-forming units, lung cytokines, and leukocytes from alveolar spaces, lung parenchyma, and gonadal adipose tissue were assessed using flow cytometry. Neutrophils from uninfected mice were cultured with and without 2-deoxy-d-glucose (2-DG) and assessed for phagocytosis, killing, reactive oxygen intermediates (ROI), transport of 2-DG, and glucose transporter (GLUT1-4) transcripts, and protein expression of GLUT1 and GLUT3. HFD mice had higher lung and splenic bacterial burdens. In HFD mice, baseline lung homogenate concentrations of IL-1ß, IL-6, IL-17, IFN-γ, CXCL2, and TNF-α were reduced relative to ND mice, but following infection were greater for IL-6, CCL2, CXCL2, and IL-1ß (24 h only). Despite equivalent lung homogenate leukocytes, HFD mice had fewer intraalveolar neutrophils. HFD neutrophils exhibited decreased Klebsiella phagocytosis and killing and reduced ROI to heat-killed Klebsiella in vitro. 2-DG transport was lower in HFD neutrophils, with reduced GLUT1 and GLUT3 transcripts and protein (GLUT3 only). Blocking glycolysis with 2-DG impaired bacterial killing and ROI production in neutrophils from mice fed ND but not HFD. Diet-induced obesity impairs pulmonary Klebsiella clearance and augments blood dissemination by reducing neutrophil killing and ROI due to impaired glucose transport.

Maternal carbohydrate intake during pregnancy is associated with child peripubertal markers of metabolic health but not adiposity.

OBJECTIVE: To examine the associations of trimester-specific maternal prenatal carbohydrate (CHO) intake with offspring adiposity and metabolic health during peripuberty. DESIGN: Prospective cohort study in which maternal dietary intake was collected via validated FFQ during each trimester. Offspring adiposity and metabolic biomarkers were evaluated at age 8-14 years. We used multivariable linear regression to examine associations between total energy-adjusted maternal CHO intake and offspring BMI z-score, skinfold thickness and metabolic syndrome risk z-score calculated as the average of waist circumference, fasting glucose, fasting C-peptide, TAG:HDL and systolic blood pressure + diastolic blood pressure/2. SETTING: Mexico City, Mexico. PARTICIPANTS: 237 mother-child pairs in the Early Life Exposure in Mexico to Environmental Toxicants cohort. RESULTS: We found non-linear associations of maternal CHO intake during pregnancy with offspring metabolic health during peripuberty. After adjusting for maternal age, and child age, sex and pubertal status, children whose mothers were in the fourth v. first quartile of total CHO intake during the third trimester had 0·42 (95 % CI -0·01, 0·08) ng/ml lower C-peptide and 0·10 (95 % CI -0·02, 0·22) units lower C-peptide insulin resistance (CP-IR). We found similar magnitude and direction of association with respect to net CHO intake during the first trimester and offspring C-peptide and CP-IR. Maternal CHO intake during pregnancy was not associated with offspring adiposity. CONCLUSIONS: In this study of mother-child pairs in Mexico City, children born to women in the highest quartile of CHO intake during pregnancy had lowest C-peptide and CP-IR during peripuberty. Additional research is warranted to replicate and identify mechanisms.

Ruminant-Related Risk Factors are Associated with Shiga Toxin-Producing Escherichia coli Infection in Children in Southern Ghana.

Livestock can provide benefits to low-income households, yet may expose children to zoonotic enteropathogens that cause illness and negative long-term health outcomes. The aim of this cross-sectional study was to determine whether livestock-related risk factors, including animal ownership, exposure to animal feces, and consumption of animal-source foods, were associated with bacterial zoonotic enteropathogen infections in children 6-59 months old in Greater Accra, Ghana. Stool samples from 259 children and 156 household chickens were analyzed for atypical enteropathogenic Escherichia coli (aEPEC), Campylobacter jejuni/coli (C. jejuni/coli), Salmonella, and Shiga toxin-producing Escherichia coli (STEC) using quantitative polymerase chain reaction (qPCR). aEPEC, C. jejuni/coli, STEC, and Salmonella were detected in 45.6%, 11.6%, 4.3%, and 0.8% of children's stool samples, respectively. In adjusted logistic regression models, household ownership of goats or sheep was associated with STEC detection in children (odds ratio [95% confidence interval]: 4.30 [1.32, 14.08]), as were positive detection of STEC in chicken feces (7.85 [2.54, 24.30]) and frequent consumption of fresh cow's milk (3.03 [1.75, 5.24]). No livestock-related risk factors were associated with aEPEC or C. jejuni/coli infection in children. Our findings suggest that ruminant ownership in southern Ghana may expose children to STEC through household fecal contamination and foodborne routes. The lack of association between livestock risk factors and the more commonly detected pathogens, aEPEC and C. jejuni/coli, warrants further research, particularly to help explain how animal-keeping and sanitation practices affect transmission of fecal pathogens that were highly prevalent in chicken feces.

Transcriptional profiling of the response to the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine revealed activation of the eIF2α/ATF4 integrated stress response in two in vitro placental models.

Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant. Although TCE exposure is prevalent, epidemiological studies of TCE exposure associations with adverse birth outcomes are inconclusive. Prior studies show that the TCE metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) exhibits toxicity in a placental cell line. In the current study, genome-wide gene expression and gene set enrichment analyses were used to identify novel genes and pathway alterations in the HTR-8/SVneo human trophoblast cell line and human placental villous explants treated with DCVC at concentrations relevant to human exposures. In the cells, concentration- and time-dependent effects were observed, as evidenced by the magnitude of altered gene expression after treatment with 20 µM DCVC versus 10 µM, and 12-h versus 6-h of treatment. Comparing the two models for the transcriptional response to 12-h 20 µM DCVC treatment, no differentially expressed genes reached significance in villous explants, whereas 301 differentially expressed genes were detected in HTR-8/SVneo cells compared with non-treated controls (FDR < 0.05 + LogFC > 0.35 [FC > 1.3]). GSEA revealed five upregulated enriched pathways in common between explants and cells (FDR < 0.05). Moreover, all 12-h DCVC treatment groups from both models contained upregulated pathways enriched for genes regulated by the ATF4 transcription factor. The overrepresentation of ATF4 regulation of differentially expressed genes indicated activation of the integrated stress response (ISR), a condition triggered by multiple stress stimuli, including the unfolded protein response. DCVC-induced ISR activation was confirmed by elevated eIF2α phosphorylation, ATF4 protein concentrations, and decreased global protein synthesis in HTR-8/SVneo cells. This study identifies a mechanism of DCVC-induced cytotoxicity by revealing the involvement of a specific stress signaling pathway.

Clinical and Genetic Risk Factors of Recurrent Nonalcoholic Fatty Liver Disease After Liver Transplantation.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has been increasingly reported among recipients of liver transplantation (LT). We aimed to identify clinical and genetic risk factors responsible for the development of early recurrent NAFLD in nonalcoholic steatohepatitis transplant recipients. METHODS: Forty-six total single nucleotide polymorphisms with known association with NAFLD were tested among both recipient and donor liver samples in 66 LT recipients with nonalcoholic steatohepatitis to characterize influences on NAFLD recurrence at ∼1 year post-LT (median interval from LT to biopsy: 377 days). RESULTS: Recurrent NAFLD was identified in 43 (65.2%) patients, 20 (30.3%) with mild recurrence, and 23 (34.8%) with moderate to severe NAFLD. On adjusted analysis, change in the body mass index (BMI) (ΔBMI) was significantly associated with NAFLD recurrence, whereas post-LT diabetes mellitus was associated with increased severity of NAFLD recurrence. ADIPOR1 rs10920533 in the recipient was associated with increased risk of moderate to severe NAFLD recurrence, whereas the minor allele of SOD2 rs4880 in the recipient was associated with reduced risk. Similar reduced risk was noted in the presence of donor SOD2 rs4880 and HSD17B13 rs6834314 polymorphism. DISCUSSION: Increased BMI post-LT is strongly associated with NAFLD recurrence, whereas post-LT diabetes mellitus was associated with increased severity of NAFLD recurrence. Both donor and recipient SOD2 rs4880 and donor HSD17B13 rs6834314 single nucleotide polymorphisms may be associated with reduced risk of early NAFLD recurrence, whereas presence of the minor allele form of ADIPOR1 rs10920533 in the recipient is associated with increased severity NAFLD recurrence.

Lactational High Fat Diet in Mice Causes Insulin Resistance and NAFLD in Male Offspring Which Is Partially Rescued by Maternal Metformin Treatment.

Maternal metabolic disease and diet during pregnancy and lactation have important implications for the programming of offspring metabolic disease. In addition, high-fat diets during pregnancy and lactation can predispose the offspring to non-alcoholic fatty liver disease (NAFLD), a rising health threat in the U.S. We developed a model of maternal high-fat feeding exclusively during the lactation period. We previously showed that offspring from dams, given lactational high-fat diet (HFD), are predisposed to obesity, glucose intolerance, and inflammation. In separate experiments, we also showed that lactational metformin treatment can decrease offspring metabolic risk. The purpose of these studies was to understand the programming implications of lactational HFD on offspring metabolic liver disease risk. Dams were fed a 60% lard-based HFD from the day of delivery through the 21-day lactation period. A subset of dams was also given metformin as a co-treatment. Starting at weaning, the offspring were fed normal fat diet until 3 months of age; at which point, a subset was challenged with an additional HFD stressor. Lactational HFD led male offspring to develop hepatic insulin resistance. The post-weaning HFD challenge led male offspring to progress to NAFLD with more severe outcomes in the lactational HFD-challenged offspring. Co-administration of metformin to lactating dams on HFD partially rescued the offspring liver metabolic defects in males. Lactational HFD or post-weaning HFD had no impact on female offspring who maintained a normal insulin sensitivity and liver phenotype. These findings indicate that HFD, during the lactation period, programs the adult offspring to NAFLD risk in a sexually dimorphic manner. In addition, early life intervention with metformin via maternal exposure may prevent some of the liver programming caused by maternal HFD.

Obesity Augments 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.

A peer evaluation training results in high-quality feedback, as measured over time in nutritional sciences graduate students.

Peer evaluation skills are not typically taught to students, yet they are expected to provide high-quality feedback to their peers. Gameful learning, a pedagogy supporting student-driven learning, can further reinforce the development of peer evaluation skills, if students are motivated to improve upon them. To better understand the effects of a peer evaluation training on the quality of student-generated peer evaluations, we scored peer evaluations from two cohorts taking a graduate-level nutritional sciences class using gameful learning pedagogy. The intervention group completed a peer evaluation training before engaging in peer reviews, while the control group did not. The training included two readings, a video, and reflection questions. The peer evaluations submitted by both the intervention and control groups were assessed on a validated rubric. The peer evaluation training had a positive effect on the quality of the submitted peer evaluations. The intervention group had a 10.8% higher score on its first submitted peer evaluation compared with controls (P = 0.003). The intervention group improved the quality of its future submissions by a further 8.9%, whereas the controls did not continue to improve substantially (P < 0.001). Overall, peer review training enhanced the quality of peer evaluations and allowed students to develop professional skills that they can utilize in any biomedical profession. Our results highlight the importance of peer evaluation training in combination with repeated practice and student-driven learning brought forth by gameful learning pedagogy in improving the quality of evaluations and developing professional skills.