Project description:The goal of the experiment was to examine hepatic gene expression differences induced by a low protein high carbohydrate diet. We used chemically defined diets based on naturally defined diets first published and completely described in Fontana et al., 2016, Cell Reports.
Project description:Proteomics of liver tissue from mice fed a high fat diet (HFD) or regular chow diet. Data accompany our paper entitled “Dynamic Regulation of N6,2′-O-dimethyladenosine (m6Am) in Obesity” scheduled for publication in Nature Communications, 2021
Project description:Type 2 diabetic cardiomyopathy (DCM) has been linked to Ca2+ signaling alterations, notably a decreased mitochondrial Ca2+ uptake. Uncovering of Ca2+ microdomains between cardiac mitochondria and reticulum launched a new investigation avenue for cardiometabolic diseases. We here aimed to study if the impairment of mitochondrial Ca2+ handling could be due to a dysregulation of the reticulum-mitochondria interactions or of the mitochondrial Ca2+ uniporter in the diabetic mice heart. Phenotypic alterations of the type 2 diabetic mouse heart, was done using an in vivo obesogenic high fat high sucrose diet fed mouse model (HFHSD: 20% proteins, 36% lipids). The composition of the cardiac MAM fractions between standard diet-fed (SD) mice and HFHSD (HF) mice at 16 weeks was analysed by MS-based quantitative proteomics.
Project description:Non-alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, we assess the metabolic and hepatic effects of dietary amino acid (AA) source in Western diet (WD)-induced NAFLD in male and female mice. The AA source was either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein-based WD displayed glucose intolerance, fasting hyperglycemia, and insulin-resistance and developed NAFLD associated with changes in hepatic gene expression and dysbiosis. In contrast, males fed the AA-based WD showed no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein-based WD. Females were protected against WD-induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. Thus, free dietary AA intake prevents the unhealthy metabolic outcomes of a WD in a sex-specific manner.
Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and TNF-a and fatty acid induced inflammatory responses in an aryl-hydrocarbon receptor (AhR) dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic TG, liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β- oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to NASH.
Project description:Microarray analysis showed dysregulation of genes involved in lipid, xenobiotic and glutathione metabolism as well as those involved in mitochondrial function and cell proliferation in the livers of C57BL6 mice fed alcoholic liquid diet for 6 weeks. We analyzed liver RNA from 4 mice fed alcoholic diet and 4 mice fed control diet using the Affymetrix Mouse Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool.
Project description:Iron is an essential nutritional element; its deficiency in the body causes nutritional problems and a decrease in iron storage that can lead to anemia. The liver not only stores iron but is an important metabolic target as well. Dietary iron deficiency is associated with changes in the metabolism of nutrients such as lipids. However, to the best of our knowledge, a global analysis detailing the consequences of iron deficiency in the body has not yet been reported. We performed a comprehensive transcriptome analysis using DNA microarray technology to reveal the effects of iron deficiency on hepatic gene expression. Four-week-old rats were fed an iron-deficient diet or a control diet for 16 days. On day 17, the rats were sacrificed under anesthesia, and their livers were dissected for DNA microarray analysis. We identified 600 up-regulated and 500 down-regulated probe sets to characterize the iron-deficient diet group. The up-regulated probe sets contained genes for enzymes that are involved in cholesterol, amino acid, and glucose metabolisms, as well as in apoptosis. The down-regulated probe sets included genes for enzymes associated with lipid metabolism. Additionally, the 16-day iron-deficient diet induced anemia. Our gene expression analysis revealed that, as a result, cholesterol biosynthesis, gluconeogenesis, and apoptosis due to endoplasmic reticulum stress were accelerated, while fatty acid biosynthesis was suppressed by dietary iron deficiency. Our analysis also showed that cholesterol metabolism, including bile acid biosynthesis, was accelerated in the initial stages of cholesterol accumulation. Experiment Overall Design: Male 3-week-old Sprague Dawley rats were purchased from Charles River Japan (Kanagawa, Japan) and housed in a room conditioned at 24 ± 1°C and 40 ± 5% humidity with a 12-h light-dark cycle (lights on at 08:00). The rats were given a control diet and water for 24 h ad libitum. Diets for rats were obtained from Research Diets, Inc. (New Brunswick, NJ, USA). The composition of the control diet was based on the AIN93G diet , except that cellulose was replaced by Avicel, since cellulose is an ingredient of variable iron content. The iron-deficient diet was prepared by removal of iron (ferric citrate) from the control diet. At day 8, rats were divided into two groups comprising animals of similar body weights. One group (n = 6) was fed the control diet and the other group (n = 7) was fed the iron-deficient diet (iron-deficient diet group). After iron-deficient diet feeding was started, blood hemoglobin levels were measured every two days. Blood samples for hemoglobin measurements were collected from the tail vein, and hemoglobin levels were measured by using the Wako Hemoglobin B test (Wako Pure Chemical Industries, Osaka, Japan). On day 12 of the iron-deficient diet treatment, diets were removed at 17:00, and feeding was conducted between 09:00 and 17:00 for another 4 days. This protocol was intended to synchronize the ratsâ feeding behavior. On day 17 of the iron-deficient diet treatment, rats were fed for 1.5 h prior to sacrifice under anesthesia. Livers were then excised and subsequently immersed in RNAlater (Applied Biosystems Japan, Tokyo, Japan). Blood hemoglobin level of rats fed an iron-deficient diet decreased significantly over the course of the feeding. On day 17, the hemoglobin level in the iron-deficient diet group was 42% of that of the control diet group (P < 0.01).
Project description:We demonstrate that the ketogenic diet a low carbohydrate diet can induce fibrosis and NASH regardless of body weight loss compared to high-fat diet (HFD) fed mice. KD-fed mice develop severe hepatic injury, inflammation, and steatosis. In addition, KD increases IL-6-JNK signaling and aggravates diet induced-glucose intolerance and hepatic insulin resistance compared to HFD. Notably, pharmacological inhibition of IL-6 and JNK reverses KD‐induced glucose intolerance and restores insulin sensitivity.