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Originally published In Press as doi:10.1074/mcp.M600120-MCP200 on January 6, 2007.
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Molecular & Cellular Proteomics 6:624-637, 2007.
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

Carbonylation of Adipose Proteins in Obesity and Insulin Resistance

Identification of Adipocyte Fatty Acid-binding Protein as a Cellular Target of 4-Hydroxynonenal*,S

Paul A. Grimsrud{ddagger}, Matthew J. Picklo, Sr.§, Timothy J. Griffin{ddagger} and David A. Bernlohr{ddagger},¶

From the {ddagger} Department of Biochemistry, Molecular Biology and Biophysics, The University of Minnesota, Minneapolis, Minnesota 55455 and § Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Science, Grand Forks, North Dakota 58203

Obesity is a state of mild inflammation correlated with increased oxidative stress. In general, pro-oxidative conditions lead to production of reactive aldehydes such as trans-4-hydroxy-2-nonenal (4-HNE) and trans-4-oxo-2-nonenal implicated in the development of a variety of metabolic diseases. To investigate protein modification by 4-HNE as a consequence of obesity and its potential relationship to the development of insulin resistance, proteomics technologies were utilized to identify aldehyde-modified proteins in adipose tissue. Adipose proteins from lean insulin-sensitive and obese insulin-resistant C57Bl/6J mice were incubated with biotin hydrazide and detected using horseradish peroxidase-conjugated streptavidin. High carbohydrate, high fat feeding of mice resulted in a ~2–3-fold increase in total adipose protein carbonylation. Consistent with an increase in oxidative stress in obesity, the abundance of glutathione S-transferase A4 (GSTA4), a key enzyme responsible for metabolizing 4-HNE, was decreased ~3–4-fold in adipose tissue of obese mice. To identify specific carbonylated proteins, biotin hydrazide-modified adipose proteins from obese mice were captured using avidin-Sepharose affinity chromatography, proteolytically digested, and subjected to LC-ESI MS/MS. Interestingly enzymes involved in cellular stress response, lipotoxicity, and insulin signaling such as glutathione S-transferase M1, peroxiredoxin 1, glutathione peroxidase 1, eukaryotic elongation factor 1{alpha}-1 (eEF1{alpha}1), and filamin A were identified. The adipocyte fatty acid-binding protein, a protein implicated in the regulation of insulin resistance, was found to be carbonylated in vivo with 4-HNE. In vitro modification of adipocyte fatty acid-binding protein with 4-HNE was mapped to Cys-117, occurred equivalently using either the R or S enantiomer of 4-HNE, and reduced the affinity of the protein for fatty acids ~10-fold. These results indicate that obesity is accompanied by an increase in the carbonylation of a number of adipose-regulatory proteins that may serve as a mechanistic link between increased oxidative stress and the development of insulin resistance.

To whom correspondence should be addressed: Dept. of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, 321 Church St. S E., Minneapolis, MN 55455. Tel.: 612-624-2712; Fax: 612-625-2163; E-mail: bernl001{at}umn.edu


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