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J. Biol. Chem., Vol. 282, Issue 20, 14807-14815, May 18, 2007

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Hepatic Overexpression of Glycerol-sn-3-phosphate Acyltransferase 1 in Rats Causes Insulin Resistance^*

Cynthia A. Nagle¹, Jie An¹, Masakazu Shiota^¶, Tracy P. Torres^¶, Gary W. Cline^||, Zhen-Xiang Liu^||, Shuli Wang, ReEtta L. Catlin^¶, Gerald I. Shulman^||**2, Christopher B. Newgard, and Rosalind A. Coleman³

From the Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599, the Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27704, the ^¶Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, and the ^||Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, and the ^**Howard Hughes Medical Institute, New Haven, Connecticut 06520

Fatty liver is commonly associated with insulin resistance and type 2 diabetes, but it is unclear whether triacylglycerol accumulation or an excess flux of lipid intermediates in the pathway of triacyglycerol synthesis are sufficient to cause insulin resistance in the absence of genetic or diet-induced obesity. To determine whether increased glycerolipid flux can, by itself, cause hepatic insulin resistance, we used an adenoviral construct to overexpress glycerol-sn-3-phosphate acyltransferase-1 (Ad-GPAT1), the committed step in de novo triacylglycerol synthesis. After 5–7 days, food intake, body weight, and fat pad weight did not differ between Ad-GPAT1 and Ad-enhanced green fluorescent protein control rats, but the chow-fed Ad-GPAT1 rats developed fatty liver, hyperlipidemia, and insulin resistance. Liver was the predominant site of insulin resistance; Ad-GPAT1 rats had 2.5-fold higher hepatic glucose output than controls during a hyperinsulinemic-euglycemic clamp. Hepatic diacylglycerol and lysophosphatidate were elevated in Ad-GPAT1 rats, suggesting a role for these lipid metabolites in the development of hepatic insulin resistance, and hepatic protein kinase C was activated, providing a potential mechanism for insulin resistance. Ad-GPAT1-treated rats had 50% lower hepatic NF-B activity and no difference in expression of tumor necrosis factor- and interleukin-, consistent with hepatic insulin resistance in the absence of increased hepatic inflammation. Glycogen synthesis and uptake of 2-deoxyglucose were reduced in skeletal muscle, suggesting mild peripheral insulin resistance associated with a higher content of skeletal muscle triacylglycerol. These results indicate that increased flux through the pathway of hepatic de novo triacylglycerol synthesis can cause hepatic and systemic insulin resistance in the absence of obesity or a lipogenic diet.

Received for publication, December 18, 2006 , and in revised form, March 27, 2007.

^* This work was supported in part by National Institutes of Health Grants DK56598 (to R. A. C.), DK-58398 (to C. B. N.), DK60667 (to M. S.), DK-40936 (to G. I. S.), U24 DK59635, and P30 DK34987, and by an award from the American Heart Association, Mid-Atlantic Affiliate (to C. A. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to the results of this work.

² Investigator of the Howard Hughes Medical Institute.

³ To whom correspondence should be addressed: Dept. of Nutrition, CB# 7461, University of North Carolina, Chapel Hill, NC 27599-7461. Tel.: 919-966-7213; Fax: 919-966-7216; E-mail: rcoleman{at}unc.edu.

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