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Vol. 18, Issue 4, 1519-1529, April 2007

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ATF-2 Regulates Fat Metabolism in Drosophila

Tomoo Okamura^*,, Hideyuki Shimizu^*, Tomoko Nagao^*, Ryu Ueda, and Shunsuke Ishii^*,

*Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan; University of Tsukuba, Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki 305-8577, Japan; and Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan

Submitted October 11, 2006; Revised January 16, 2007; Accepted February 2, 2007
Monitoring Editor: William Tansey

ATF-2 is a member of the ATF/CREB family of transcription factors that is activated by stress-activated protein kinases such as p38. To analyze the physiological role of Drosophila ATF-2 (dATF-2), we generated dATF-2 knockdown flies using RNA interference. Reduced dATF-2 in the fat body, the fly equivalent of the mammalian liver and adipose tissue, decreased survival under starvation conditions. This was due to smaller triglyceride reserves of dATF-2 knockdown flies than control flies. Among multiple genes that control triglyceride levels, expression of the Drosophila PEPCK (dPEPCK) gene was strikingly reduced in dATF-2 knockdown flies. PEPCK is a key enzyme for both gluconeogenesis and glyceroneogenesis, which is a pathway required for triglyceride synthesis via glycerol-3-phosphate. Although the blood sugar level in dATF-2 knockdown flies was almost same as that in control flies, the activity of glyceroneogenesis was reduced in the fat bodies of dATF-2 knockdown flies. Thus, reduced glyceroneogenesis may at least partly contribute to decreased triglyceride stores in the dATF-2 knockdown flies. Furthermore we showed that dATF-2 positively regulated dPEPCK gene transcription via several CRE half-sites in the PEPCK promoter. Thus, dATF-2 is critical for regulation of fat metabolism.

Address correspondence to: Shunsuke Ishii (sishii{at}rtc.riken.jp)

Abbreviations used: ACC, acetyl coenzyme A carboxylase; AcCoAS, acetyl coenzyme A synthetase; ATF, activating transcription factor; BBF, box B-binding factor; CRE, cyclic AMP response element; CREB, CRE-binding protein; da, daughterless against; dATF-2, Drosophila ATF-2; dp38, Drosophila p38; dsRNA, double-stranded RNA; FAS, fatty acid synthetase; G4, Gal4; IR, inverted repeat; JNK, c-Jun N-terminal protein kinase; MAPK, mitogen-activated protein kinase; MHC, myosin heavy chain; PEPCK, phosphoenolpyruvate carboxykinase; MKP, MAPK phosphatase; RNAi, RNA interference; SAPK, stress-activated protein kinase; WAT, white adipose tissue.

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