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Second-generation antisense oligonucleotides against ?-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance.


ABSTRACT: Although mutations in the Wnt/?-catenin signaling pathway are linked with the metabolic syndrome and type 2 diabetes in humans, the mechanism is unclear. High-fat-fed male C57BL/6 mice were treated for 4 wk with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of ?-catenin. ?-Catenin mRNA decreased by ?80% in the liver and by 70% in white adipose tissue relative to control ASO-treated mice. ?-Catenin ASO improved hepatic insulin sensitivity and increased insulin-stimulated whole body glucose metabolism, as assessed during hyperinsulinemic-euglycemic clamp in awake mice. ?-Catenin ASO altered hepatic lipid composition in high-fat-fed mice. There were reductions in hepatic triglyceride (44%, P < 0.05) and diacylglycerol content (60%, P < 0.01) but a 30% increase in ceramide content (P < 0.001). The altered lipid content was attributed to decreased expression of sn-1,2 diacylglycerol acyltransferase and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase and an increase in serine palmitoyl transferase. The decrease in cellular diacyglycerol was associated with a 33% decrease in PKC? activation (P < 0.05) and 64% increase in Akt2 phosphorylation (P < 0.05). In summary, Reducing ?-catenin expression decreases expression of enzymes involved in hepatic fatty acid esterification, ameliorates hepatic steatosis and lipid-induced insulin resistance.

SUBMITTER: Popov VB 

PROVIDER: S-EPMC4750414 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Second-generation antisense oligonucleotides against β-catenin protect mice against diet-induced hepatic steatosis and hepatic and peripheral insulin resistance.

Popov Violeta B VB   Jornayvaz Francois R FR   Akgul Emin O EO   Kanda Shoichi S   Jurczak Michael J MJ   Zhang Dongyan D   Abudukadier Abulizi A   Majumdar Sachin K SK   Guigni Blas B   Petersen Kitt Falk KF   Manchem Vara Prasad VP   Bhanot Sanjay S   Shulman Gerald I GI   Samuel Varman T VT  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20151207 3


Although mutations in the Wnt/β-catenin signaling pathway are linked with the metabolic syndrome and type 2 diabetes in humans, the mechanism is unclear. High-fat-fed male C57BL/6 mice were treated for 4 wk with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) to decrease hepatic and adipose expression of β-catenin. β-Catenin mRNA decreased by ≈80% in the liver and by 70% in white adipose tissue relative to control ASO-treated mice. β-Catenin ASO improved hepatic insulin sensitivity  ...[more]

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