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The Journal of Neuroscience, December 10, 2008, 28(50):13640-13648; doi:10.1523/JNEUROSCI.4023-08.2008

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Behavioral/Systems/Cognitive
Monitoring FoxO1 Localization in Chemically Identified Neurons

Makoto Fukuda,¹ Juli E. Jones,² David Olson,² Jennifer Hill,¹ Charlotte E. Lee,¹ Laurent Gautron,¹ Michelle Choi,¹ Jeffrey M. Zigman,¹ Bradford B. Lowell,² and Joel K. Elmquist¹

¹Division of Hypothalamic Research, Departments of Internal Medicine, Pharmacology, and Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9077, and ²Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Correspondence should be addressed to Dr. Joel K. Elmquist, Division of Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9077. Email: Joel.Elmquist{at}UTSouthwestern.edu

The PI3K-Akt-FoxO1 pathway contributes to the actions of insulin and leptin in several cell types, including neurons in the CNS. However, identifying these actions in chemically identified neurons has proven difficult. To address this problem, we have developed a reporter mouse for monitoring PI3K-Akt signaling in specific populations of neurons, based on FoxO1 nucleocytoplasmic shuttling. The reporter, FoxO1 fused to green fluorescent protein (FoxO1GFP), is expressed under the control of a ubiquitous promoter that is silenced by a loxP flanked transcriptional blocker. Thus, the expression of the reporter in selected cells is dependent on the action of Cre recombinase. Using this model, we found that insulin treatment resulted in the nuclear exclusion of FoxO1GFP within POMC and AgRP neurons in a dose- and time-dependent manner. FoxO1GFP nuclear exclusion was also observed in POMC neurons following in vivo administration of insulin. In addition, leptin induced transient nuclear export of FoxO1GFP in POMC neurons in a dose dependent manner. Finally, insulin-induced nuclear export was impaired in POMC neurons by pretreatment with free fatty acids, a paradigm known to induce insulin resistance in peripheral insulin target tissues. Thus, our FoxO1GFP mouse provides a tool for monitoring the status of PI3K-Akt signaling in a cell-specific manner under physiological and pathophysiological conditions.

Key words: FoxO1; POMC neurons; AgRP neurons; insulin; free fatty acids; insulin resistance

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Received Aug. 22, 2008; revised Oct. 16, 2008; accepted Oct. 16, 2008.

Correspondence should be addressed to Dr. Joel K. Elmquist, Division of Hypothalamic Research, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9077. Email: Joel.Elmquist{at}UTSouthwestern.edu

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