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An iTRAQ Proteomic Study Reveals an Association between Diet-induced Enhanced Fatty-acid Metabolism and the Development of Glucose Intolerance in Prediabetic Mice.
MedLine Citation:
PMID:  23316967     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
High-fat diet (HFD)-induced glucose intolerance and insulin resistance increases the chances of developing type-2 diabetes and cardiovascular disease. To study the mechanism(s) by which a HFD impairs glucose tolerance, we used a quantitative proteomic platform that integrated pI-based OFFGEL fractionation and iTRAQ labeling to profile the temporal changes in adipose membrane protein expression in mice fed a HFD for up to 8 months. Within 2 months of starting the diet, the mice adipose and liver tissues accumulated fat droplets, which contributed to subsequent insulin resistance and glucose intolerance within 6 months. The membrane proteomics delineation of such phenotypic expression resulted in quantification of 1713 proteins with 266, 343 and 125 differentially expressed proteins in 2-, 6-, and 8-month HFD-fed versus control mice, respectively. Pathway analysis of these differentially expressed proteins revealed the interplay between up-regulation of fatty acid metabolism and down-regulation of glucose metabolism. Substantial upregulation of adipose and liver carnitine palmitoyltransferase (Cpt) 1, the rate-limiting enzyme in the transport of long-chain fatty acids into mitochondria, occurred by 2 months. The increase in hepatic Cpt 1a expression was associated with a progressive decrease in glucose uptake as evidenced by downregulation of the liver glucose transporter protein (Glut) 2. Loss of glycogen storage was found in those hepatocytes full of fat droplets. Intriguingly, skeletal muscle Cpt 1b expression was unaltered by the HFD, whereas skeletal muscle Glut 4 and tyrosine phosphoryated insulin receptor substrate 1 (p-IRS1) were substantially upregulated at the same time as abnormal glucose metabolism developed in adipose and liver tissues. This study defines some of the molecular mechanisms as well as the relationship among adipose tissue, liver and skeletal muscle during development of HFD-induced glucose intolerance in vivo and identifies Cpt 1 as a potential drug target for the control or prevention of diabetes.
Authors:
Jennifer H Ho; Oscar K Lee; Yun-Ju Fu; Hung-Ta Shih; Chien-Yu Tseng; Cheng-Chih Chung; Chia-Li Han; Yu-Ju Chen
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-15
Journal Detail:
Title:  Journal of proteome research     Volume:  -     ISSN:  1535-3907     ISO Abbreviation:  J. Proteome Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101128775     Medline TA:  J Proteome Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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