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J. Biol. Chem., Vol. 279, Issue 52, 53915-53923, December 24, 2004

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Leucine Culture Reveals That ATP Synthase Functions as a Fuel Sensor in Pancreatic -Cells^*

Jichun Yang, Ryan K. Wong, Xujing Wang, Jacob Moibi, Martin J. Hessner, Scott Greene, Jianmei Wu, Siam Sukumvanich, Bryan A. Wolf, and Zhiyong Gao¶

From the Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Our goal was to investigate whether leucine culture affects -cell glucose sensing. One-day culture of rat islets with 10 mM leucine had no effect on glucose-induced insulin secretion. One-week leucine culture decreased the threshold for glucose-induced insulin secretion and increased maximal insulin secretion at 30 mM glucose. Glucose-induced cytosolic free Ca²⁺ was increased at 1 week but not at 1 day of leucine culture. Without glucose, ATP content was not different with or without leucine culture for 1 week. With 20 mM glucose, ATP content was higher by 1.5-fold in islets cultured for 1 week with leucine than those without leucine. Microarray experiments indicated that culture of RINm5F cells with leucine increased expression of ATP synthase subunit 3.2-fold, which was confirmed by real time reverse transcription-PCR analysis (3.0- ± 0.4-fold) in rat islets at 1 week but not after 1 day with leucine culture. Down-regulation of ATP synthase subunit by siRNA decreased INS1 cell ATP content and insulin secretion with 20 mM glucose. Overexpression of ATP synthase subunit in INS1 cell increased insulin secretion in the presence of 5 and 20 mM glucose. In conclusion, one-week leucine culture of rat islets up-regulated ATP synthase and increased ATP content, which resulted in elevated [Ca²⁺] levels and more insulin exocytosis by glucose. Depletion of ATP synthase subunit with siRNA produced opposite effects. These data reveal the fuel-sensing role of mitochondrial ATP synthase in the control of ATP production from glucose and the control of glucose-induced insulin secretion.

Received for publication, May 12, 2004 , and in revised form, October 1, 2004.

^* 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.

^¶ To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, 803 Abramson, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318. Tel: 215-590-7301; Fax: 215-590-7377; E-mail: gao{at}email.chop.edu.

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