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High fat diet-induced modifications in membrane lipid and mitochondrial-membrane protein signatures precede the development of hepatic insulin resistance in mice

ABSTRACT: In this survey we effectively combined transcriptomics, proteomics and targeted-metabolomics to analyse the temporal relationship of alterations in liver preceding and accompanying the development of HFD-mediated hepatic insulin resistance. To assess HFD-mediated alterations in physiological parameters, insulin sensitivity, and molecular adaptations in liver male C3HeB/FeJ mice treated with a high-fat diet (HFD) for 7, 14, or 21 days and compared to age- matched controls fed low-fat diet (LFD). Data indicate early systemic increases in pro-inflammatory signals, in hepatic DAG but not hepatic TAG concentrations prior to development of hepatic insulin resistance. We propose a hypothesis via which a HFD-mediated increase in the hepatic long-chain acyl-carnitine moiety in liver alters mitochondrial membrane physiology and beta-oxidation rates, thereby contributing to oxidative stress and the development of insulin resistance in liver. Alterations in the enrichment of respiratory chain complex proteins, substrate transporters, VDACs, and long-chain carnitines in mitochondrial membranes likely affect mitochondrial membrane topology, membrane dynamics (fission and fusion) and bioenergetics as well as the cross-talk between the mitochondria and other cellular compartments. In conclusion, we emphasize a tight association between HFD-induced early modifications in the organisation of mitochondrial membranes paving the road for hepatic insulin resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE48615 | GEO | 2018/03/08

REPOSITORIES: GEO

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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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High fat diet-induced modifications in membrane lipid and mitochondrial-membrane protein signatures precede the development of hepatic insulin resistance in mice

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