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J. Biol. Chem., Vol. 283, Issue 21, 14248-14256, May 23, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/21/14248    most recent M800119200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ronnebaum, S. M. Articles by Newgard, C. B. PubMed PubMed Citation Articles by Ronnebaum, S. M. Articles by Newgard, C. B. Social Bookmarking                      What's this?

Chronic Suppression of Acetyl-CoA Carboxylase 1 in β-Cells Impairs Insulin Secretion via Inhibition of Glucose Rather Than Lipid Metabolism^*

Sarah M. Ronnebaum, Jamie W. Joseph, Olga Ilkayeva, Shawn C. Burgess, Danhong Lu, Thomas C. Becker, A. Dean Sherry, and Christopher B. Newgard¹

From the Sarah W. Stedman Nutrition and Metabolism Center and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27704 and Departments of Radiology and Pharmacology, Mary Nell and Ralph B. Rogers Magnetic Resonance Center and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75235

Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60–80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to β-cells suppressed [¹⁴C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.

Received for publication, January 7, 2008 , and in revised form, March 19, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK42583 (to C. B. N.) and DK58398 (to C. B. N. and A. D. S.). 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 To whom correspondence should be addressed: Sarah W. Stedman Nutrition and Metabolism Ctr., Duke Independence Park Facility, 4321 Medical Park Dr., Suite 200, Durham, NC 27704. Fax: 919-477-0632; E-mail: newga002{at}mc.duke.edu.

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