Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling by array of adipose samples from LDLR-/- mice to study response to anti-diabetic drug and dietary lifestyle interventions

ABSTRACT: Lean male mice were fed a high fat diet (HFD, lard 24% w/w) for 16 weeks. At 9 weeks, when all hallmarks of prediabetes were established, groups of mice were treated with drug (rosiglitazone, pioglitazone, T0901317, or salicylate) for another 7 weeks together with the high fat diet. An additional group was switched back to a chow diet (dietary lifestyle intervention) after the first 9 weeks of high fat diet. All groups were compared to a control group receiving HFD alone and to a reference group fed chow (baseline reference) for the entire experimental period (16 weeks). One group (n=9) remained on maintenance chow throughout the entire study period (16 weeks) and served as healthy, age-matched control. After the nine week run-in period, the HFD fed mice were matched into thirteen groups based on body weight. The first group (n=9) was sacrificed immediately after matching. The second group (n=15) was continued on HFD until the end of the experiment at t=16 weeks. The fourth group (n=9) was switched to regular chow (dietary lifestyle intervention). The other groups (each n=9) continued on HFD supplemented with drugs typically used in clinical practice. More specifically, following drugs were mixed into HFD ; rosiglitazone (0.010% w/w), pioglitazone (0.010% w/w), T0901317 (0.010% w/w) and salicylate (0.40% w/w).

ORGANISM(S): Mus musculus

SUBMITTER: Thomas Kelder

PROVIDER: E-GEOD-57659 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Differential effects of drug interventions and dietary lifestyle in developing type 2 diabetes and complications: a systems biology analysis in LDLr-/- mice.

Radonjic Marijana M Wielinga Peter Y PY Wopereis Suzan S Kelder Thomas T Goelela Varshna S VS Verschuren Lars L Toet Karin K van Duyvenvoorde Wim W van der Werff van der Vat Bianca B Stroeve Johanna H M JH Cnubben Nicole N Kooistra Teake T van Ommen Ben B Kleemann Robert R

PloS one 20130215 2

Excess caloric intake leads to metabolic overload and is associated with development of type 2 diabetes (T2DM). Current disease management concentrates on risk factors of the disease such as blood glucose, however with limited success. We hypothesize that normalizing blood glucose levels by itself is insufficient to reduce the development of T2DM and complications, and that removal of the metabolic overload with dietary interventions may be more efficacious. We explored the efficacy and systems ...[more]

PMID: 23457508

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Project description:Individuals with hepatic steatosis often display several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance via inter-organ crosstalk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy via effects on muscle protein turnover. To investigate this, eight-week-old male C57BL/6J mice were fed a chow (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into ~200 µm slices. Slices were cultured to collect secretion products (conditioned medium; CM). Differentiated L6-GLUT4myc myotubes were incubated with chow or HFD CM to measure glucose uptake. Differentiated C2C12 myotubes were incubated with chow or HFD CM to measure protein synthesis and breakdown, and gene expression via RNA sequencing. Furthermore, proteomics analysis was performed in chow and HFD CM. It was found that HFD CM caused insulin resistance in L6-GLUT4myc myotubes compared with chow CM, as indicated by a blunted insulin-stimulated increase in glucose uptake. Furthermore, protein breakdown was increased in C2C12 cells incubated with HFD CM, while there was no effect on protein synthesis. RNA profiling of C2C12 cells indicated that 197 genes were differentially expressed after incubation with HFD CM, compared with chow CM, and pathway analysis showed that pathways related to anatomical structure and function were enriched. Proteomic analysis of the CM showed that 32 proteins were differentially expressed in HFD CM compared with chow CM. Pathway enrichment analysis indicated that these proteins had important functions with respect to insulin-like Growth Factor transport and uptake, and affect post-translational processes, including protein folding, protein secretion and protein phosphorylation. In conclusion, the results of this study support the hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis.

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Dataset Information

Transcription profiling by array of adipose samples from LDLR-/- mice to study response to anti-diabetic drug and dietary lifestyle interventions

Publications

Differential effects of drug interventions and dietary lifestyle in developing type 2 diabetes and complications: a systems biology analysis in LDLr-/- mice.

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