MicroRNA data from high-fat diet fed mice with and without exercise
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus synthetic construct
PROVIDER: GSE65978 | GEO | 2017/02/09
SECONDARY ACCESSION(S): PRJNA275623
REPOSITORIES: GEO
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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.
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Project description:The increasing consumption of high-fat western foods combined with a lack of exercise is a major contributor to the burden of obesity in humans. Aerobic exercise such as running is known to provide metabolic benefits, but how the over-consumption of a high fat diet (HFD) and exercise interact is not well characterized at the molecular level. Here, we examined the plasma proteome in mice for the effects of aerobic exercise as both a treatment and as a preventative regime for animals on either HFD or a healthy control diet. This analysis detected large changes in the plasma proteome induced by the HFD intervention, such as increased abundance of SERPINA7, ALDOB, APOE, and down-regulation of SERPINA1E, CFD (adipsin), LIFR. Some of these changes were only significantly reverted using aerobic exercise as a preventative measure, but not as a treatment regime. To determine if either the intensity, or duration, of exercise influenced the outcome, we compared high-intensity interval training (HIIT) and endurance running. Endurance running slightly outperformed HIIT exercise, but overall both provided similar reversion in abundance of plasma proteins modulated by the high-fat diet including SERPINA7, APOE, SERPINA1E, and CFD. Finally, we compared the changes induced by over-consumption of HFD to previous data from mice fed an isocaloric high saturated fat (SFA) or polyunsaturated fat (PUFA) diet. This identified several common changes including increased APOC2 and APOE, but also highlighted changes specific for either over-consumption of HFD (ALDOB, SERPINA7, CFD), SFA-based diets (SERPINA1E), or PUFA-based diets (Haptoglobin - Hp). Together, these data highlight the importance of early intervention with exercise to revert HFD-induced phenotypes and suggest some of the molecular mechanisms leading to the changes in the plasma proteome generated by high fat diet consumption in both mice and humans.
2020-11-02 | PXD018561 | Pride
Project description:Background: Non-alcoholic steatohepatitis (NASH) has become one of the most common liver diseases and is still without approved pharmacotherapy. Lifestyle interventions using exercise and diet change remain the current treatment of choice and even a small weight loss (5-7%) can already have a beneficial effect on NASH. However#the underlying molecular mechanisms of exercise and diet interventions remain largely elusive#and it is unclear whether they exert their health effects via similar or different pathways. Methods: Ldlr-/-.Leiden mice received a high fat diet (HFD) for 30 weeks to establish an advanced state of NASH/fibrosis with simultaneous atherosclerosis development. Groups of mice were then either left untreated (control group) or were treated for 20 weeks with exercise (running wheel)#diet change (switch to a low fat chow diet) or the combination thereof. The liver and distant organs including heart#white adipose tissue (WAT) and muscle were histologically examined. Comprehensive transcriptome analysis of liver#WAT and muscle revealed the organ-specific effects of exercise and diet and defined the underlying pathways. Results: Exercise and dietary change significantly reduced body weight#fat mass#adipocyte size and improved myosteatosis and muscle function with additive effects of combination treatment. WAT inflammation was significantly improved by diet change#tended to be reduced with exercise#and combination therapy had no additive effect. Hepatic steatosis and inflammation were almost fully reversed by exercise and diet change#while hepatic fibrosis tended to be improved with exercise and was significantly improved with diet change. Additive effects for the combination therapy were shown for liver steatosis and associated liver lipids#and atherosclerosis#but not for hepatic inflammation and fibrosis. Pathway analysis revealed complementary effects on metabolic pathways and lipid handling processes#thereby substantiating the added value of combined lifestyle treatment. Conclusions: Exercise#diet change and the combination thereof can reverse established NASH/fibrosis in obese Ldlr-/-.Leiden mice. In addition#the lifestyle interventions had beneficial effects on atherosclerosis#WAT inflammation and muscle function. For steatosis and other parameters related to adiposity or lipid metabolism#exercise and dietary change affected more distinct pathways that acted complementary when the interventions were combined resulting in an additive effect for the combination therapy on important endpoints including NASH and atherosclerosis. For inflammation#exercise and diet change shared several underlying pathways resulting in a net similar effect when the interventions were combined.
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