Differential hepatic gene expression in a polygenic mouse model with insulin resistance and hyperglycemia: evidence for a combined transcriptional dysregulation of gluconeogenesis and fatty acid synthesis.

Institute of Pharmacology and Toxicology, Medical Faculty of Aachen University, Wendlingweg 2, D-52074 Aachen, Germany.
Journal of Molecular Endocrinology (Impact Factor: 3.62). 03/2004; 32(1):195-208.
Source: PubMed

ABSTRACT New Zealand obese (NZO) mice exhibit severe insulin resistance of hepatic glucose metabolism. In order to define its biochemical basis, we studied the differential expression of genes involved in hepatic glucose and lipid metabolism by microarray analysis. NZOxF1 (SJLxNZO) backcross mice were generated in order to obtain populations with heterogeneous metabolism but comparable genetic background. In these backcross mice, groups of controls (normoglycemic/normoinsulinemic), insulin-resistant (normoglycemic/hyperinsulinemic) and diabetic (hyperglycemic/hypoinsulinemic) mice were identified. At 22 weeks, mRNA was isolated from liver, converted to cDNA, and used for screening of two types of cDNA arrays (high-density filter arrays and Affymetrix oligonucleotide microarrays). Differential gene expression was ascertained and assessed by Northern blotting. The data indicate that hyperinsulinemia in the NZO mouse is associated with: (i) increased mRNA levels of enzymes involved in lipid synthesis (fatty acid synthase, malic enzyme, stearoyl-CoA desaturase) or fatty acid oxidation (cytochrome P450 4A14, ketoacyl-CoA thiolase, acyl-CoA oxidase), (ii) induction of the key glycolytic enzyme pyruvate kinase, and (iii) increased mRNA levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. These effects were enhanced by a high-fat diet. In conclusion, the pattern of gene expression in insulin-resistant NZO mice appears to reflect a dissociation of the effects of insulin on genes involved in glucose and lipid metabolism. The data are consistent with a hypothetical scenario in which an insulin-resistant hepatic glucose production produces hyperinsulinemia, and an enhanced insulin- and substrate-driven lipogenesis further aggravates the deleterious insulin resistance of glucose metabolism.

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Available from: Hans-Georg Joost, Jul 18, 2014
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    • "). HFHC diets have been extensively utilized for murine models of obesity, diabetes, and fatty liver. Mice fed this diet develop obesity and many of the components of the metabolic syndrome in a strain-specific manner (Minkina et al. 2012; Jiang et al. 2005; Becker et al. 2004; Schmid et al. 2004; Kobayashi et al. 2004; Rangnekar et al. 2006). In this study, A/J and C57BL/6J "
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    ABSTRACT: Die New Zealand Obese (NZO)-Maus zeigt ein dem menschlichen metabolischen Syndrom ähnliches, polygenes Krankheitssyndrom mit Adipositas und Insulinresistenz. Um die biochemischen Grundlagen dieses Krankheitsbildes aufzuklären, sollte die differentielle Expression von im hepatischen Glucose- und Lipidstoffwechsel involvierten Genen untersucht werden. Es wurde ein Kreuzungsmodell aus dem adipösen NZO- und dem normgewichtigen SJL-Stamm etabliert. Eine Rückkreuzung NZOxF1 (SJLxNZO) wurde generiert, um eine Population mit unterschiedlichen Stoffwechselparametern auf vergleichbarem genetischen Hintergrund zu erhalten. Die Tiere wurden in drei Gruppen eingeteilt: Normal (normoglykämisch/normoinsulinämisch), Insulinresistenz (normoglykämisch/hyperinsulinämisch) und Diabetes (hyperglykämisch/hypoinsulinämisch). Als Kontrolle wurden SJL-Parentaltiere verwendet. Ein Teil der Tiere wurde mit fettreichem, ein anderer Teil mit Standardnagerfutter gefüttert. Im Alter von 22 Wochen wurden die Tiere getötet und die Leber-RNA isoliert. Die differentielle Expression von Genen, die aus unterschiedlichen Gründen ausgewählt worden waren (Array-Untersuchungen, Literatursuche, Genlokalisation nahe eines Diabeteslocus), wurde in Northern und Dot blots untersucht. Dabei stellte sich heraus, dass 1) in der Insulinresistenz die Expression von Enzymen der Lipogenese und von Enzymen der Fettsäureoxidation gleichzeitig gesteigert ist, während 2) die Gluconeogenese nicht reprimiert ist, 3) fettreiche Fütterung die Lipogenese weiter steigert und 4) verschiedene Enzyme einen Geschlechtsdimorphismus aufweisen (SCPx, PLTP, Hsd3b5). Die Genexpression in der Insulinresistenz spiegelt einen dissoziierten Effekt der Insulinwirkung auf in Glucose- und Lipidstoffwechsel involvierte Gene wieder: eine durch Insulin nicht reprimierbare hepatische Glucoseproduktion führt zu Hyperinsulinämie, welche die weiterhin insulinsensitive Lipogenese fördert und dadurch die Insulinresistenz im Sinne eines Circulus vitiosus steigert. Untersuchung der differenziellen Expression der Adipokine Leptin und Resistin im Fettgewebe zeigte eine mit dem BMI korrelierte Leptin-mRNA-Menge und keine Unterschiede in der Genexpression von Resistin. New Zealand Obese (NZO) mice exhibit a polygenic syndrome of morbid obesity and insulin resistance, that resembles the human metabolic syndrome. In order to define its biochemical basis, the differential expression of genes involved in hepatic glucose and lipid metabolism was studied. An outcross model of obese NZO mice with the lean SJL strain was established. NZOxF1 (SJLxNZO) backcross mice were generated in order to obtain a population with heterogeneous metabolism but comparable genetic background. Groups of normal (normoglycemic/normoinsulinemic), insulin-resistant (normoglycemic/hyperinsulinemic) and diabetic (hyperglycemic/hypoinsulinemic) mice were identified. Parental SJL-mice were used as control. Mice received high fat or standard diet. At 22 weeks, mice were killed and RNA isolated from liver. Differential gene expression of genes chosen for various reasons (array-analysis, literature search and gene localization near a diabetogenic locus) was assessed by Northern and Dot blotting. The data indicate that 1) insulin resistance is associated with increased expression of enzymes involved in lipogenesis and in fatty acid oxidation, whereas 2) gluconeogenic enzymes are not repressed, 3) high fat diet enhanced lipid synthesis, 4) several enzymes display sex dimorphism (SCPx, PLTP, Hsd3b5). The gene expression in insulin resistance reflects a dissociation of the effects of insulin on genes involved in glucose and lipid metabolism in liver: insulin-resistant hepatic glucose production causes hyperinsulinemia, which then enhances lipogenesis and thus further aggravates insulin resistance in a circulus vitiosus. Analysis of differential expression of the adipokines leptin and resistin in adipocytes displays a correlation between BMI and leptin-mRNA and no differences in resistin gene expression.
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