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.

Project description:Adipose tissue inflammation and atherosclerosis are the main mechanisms behind type 2 diabetes and cardiovascular disease respectively, the major risks associated with the metabolic syndrome. Studies considering more than single factors behind the complexity of the metabolic syndrome are valuable to achieve a better and wider understanding of the metabolic syndrome. In this study common dysregulated pathways between adipose tissue inflammation and atherosclerosis were identified using two different bioinformatic tools to perform pathway analysis. First, we run a gene set enrichment analysis utilizing with data from two microarray experiments done with gonadal white adipose tissue and atherosclerotic aorta. Once the common dysregulated pathways between both tissues were identify, the inflammatory response and the oxidative phosphorylation pathways from the Hallmark geneset were selected to conduct a deeper checkup at the single gene level of these pathways. Second, we carried out a pathway analysis validation with the Pantherâ¢ software combining the microarray data with a published type 2 diabetes mellitus metanalysis and cardiovascular disease metanalysis which included human data. In conclusion, this study provides worthwhile data pointing out and describing several dysregulated and common pathways in adipose tissue inflammation and atherosclerotic aorta with a potential implication in the pathogenesis of type 2 diabetes and atherosclerosis. LDLR-/- on a C57BL/6J background, purchased from Charles River Laboratories (Sulzfeld, Germany) were used. At 9 weeks of age the LDLR-/- were placed for up to 20 weeks on sucrose-enriched high-fat diet (HFSC) (with 17.5 kcal% from sucrose; (D09071704, Research Diets Inc.). Their respective controls were kept on normal chow diet (NC) for up to 20 weeks. After sacrificing the gonadal white adipose tissue (GWAT) from LDLR-/- animals on NC (Samples 22-27) or HFSC (Samples 28-33) was collected as well as the whole aortae from LDLR-/- animals on NC (Samples 13-15) or HFSC (Samples16-18). The collected tissues were immediately snap frozen in liquid nitrogen. RNA was isolated for gene expression microarray analyses at the exon level (GeneChip Mouse Exon 2.0 ST Array, Affymetrix, Santa Clara, CA, USA). To isolate RNA, the frozen tissue samples were homogenized in TRIzolÂ® reagent (Invitrogen/Life Technologies, Carlsbad, CA, USA) and processed based on manufacturerâs instructions. Total RNA (1Î¼g) was then used for GeneChip analysis, individual samples were used in GWAT preparation and three samples were pooled and used for aorta preparations. Terminal-labeled cDNA, hybridization to genome-wide Mouse Gene 2.0 ST Gene Chips and scanning of the arrays were carried out according to the manufactureâs indications (Affymetrix).Output primary row data was analyzed with Expression Console software (Affymetrix).

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Mus musculus

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