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Transcriptome profiling of mutant INS gene-induced diabetes of youth (MIDY) and wild type pig livers.

ABSTRACT: Physiologically the liver is exposed to higher insulin concentrations than other organs. To evaluate functional consequences of insulin-deficient diabetes mellitus for the liver, we used a genetically engineered pig model of mutant INS gene induced diabetes of youth (MIDY). Liver samples of MIDY pigs and wild-type (WT) littermate controls were analyzed by RNA sequencing, label-free proteomics and targeted metabolomics/lipidomics to reveal pathways and key drivers significantly affected by chronic insulin deficiency and hyperglycemia. Gene set enrichment analysis of the ~500 transcripts that were differently abundant between MIDY and WT samples revealed pathways related to amino acid metabolism, beta-oxidation of fatty acids, gluconeogenesis and ketogenesis to be enriched in MIDY samples, whereas pathways related to extra cellular matrix and inflammation/pathogen defense response were enriched in the WT samples. Reduced insulin receptor activation and phosphorylation of protein kinase B (PKB, AKT) was associated with markedly increased levels of retinol dehydrogenase 16 (RDH16) and 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2), the apparent key drivers of stimulated gluconeogenesis and ketogenesis in MIDY pigs. Profiling of acylcarnitines provided evidence for increased activity of carnitine palmitoyltransferase 1 (CPT1) shuttling fatty acids into the mitochondrial matrix for beta-oxidation and for increased omega-oxidation. In addition, several enzymes involved in amino acid degradation and enzymes of the urea cycle were increased in abundance, consistent with an increased use of amino acids for gluconeogenesis. Transcripts and proteins related to extracellular matrix, such as collagens, and inflammatory/immune mechanisms, such as C-reactive protein, proteins involved in or regulated by Toll-like receptor signaling and components of major histocompatibility complexes, were less abundant in MIDY vs. WT liver samples. Our study provides the first multi-omics analysis of liver in a clinically relevant large animal model for insulin-deficient diabetes mellitus.

ORGANISM(S): Sus scrofa

PROVIDER: GSE122029 | GEO | 2020/01/01

REPOSITORIES: GEO

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Project description:Dietary polyunsaturated fatty acids (PUFA) act as potent natural hypolipidemics and are linked to many health benefits in humans and in animal models. Mice fed long-term a high fat diet, in which medium-chain alpha linoleic acid (ALA) was partially replaced by long-chain docosahexaenoic (DHA) and eicosapentaenoic (EPA) fatty acids, showed reduced accumulation of body fat and prevention of insulin resistance, besides increased mitochondrial beta-oxidation in white adipose tissue and decreased plasma lipids. ALA, EPA and DHA all belong to PUFA of n-3 series. The intestine is a gatekeeper organ for ingested lipids. To examine the potential contribution of the intestine in the beneficial effects of EPA and DHA, this study assessed gene expression changes using whole genome microarray analysis on small intestinal scrapings. The main biological process affected was lipid metabolism. Fatty acid uptake, peroxisomal and mitochondrial beta-oxidation, and omega-oxidation of fatty acids were all increased. Quantitative real time PCR and intestinal fatty acid oxidation measurements ([14C(U)]-palmitate) confirmed significant gene expression differences in a dose-dependent manner. Furthermore, no major changes in the expression of lipid metabolism genes were observed in colonic scrapings. In conclusion, we show that marine n-3 fatty acids regulate small intestinal gene expression patterns. Since this organ contributes significantly to whole organism energy use, this adaptation of the small intestine may contribute to the complex and observed beneficial physiological effects of these natural compounds under conditions that will normally lead to development of obesity and diabetes. Experiment Overall Design: Male 4-month-old C57BL/6J mice were maintained for 4 weeks on semisynthetic high-fat (20% wt/wt) diets differing in the composition of n-3 PUFA. Two isocaloric diets were used (n=12): control sHFf diet which contained flax-seed oil (rich in ALA) as the only lipid source, or the sHFf-F2 diet, which had the same composition except that 44 % of the lipids were replaced by a n-3 PUFA concentrate (EPA&DHA) containing 6 % EPA and 51 % DHA (EPAX 1050TG; EPAX AS, Lysaker, Norway). Quality control of RNA samples showed that four samples did not pass quality thresholds, and these samples were excluded from array analysis (two control small intestine samples and one EPA&DHA small intestine sample). The remaining RNA samples were pooled per tissue per diet group. Thus; the flax-seed (control) array was hybridized with RNA pooled from of 10 mice, the PUFA array was hybridized with RNA pooled from 11 mice.

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Transcriptome profiling of mutant INS gene-induced diabetes of youth (MIDY) and wild type pig livers.

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