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Molecular and Cellular Biology, March 2009, p. 1363-1374, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.00705-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

SIRT1 Exerts Anti-Inflammatory Effects and Improves Insulin Sensitivity in Adipocytes ^,

Takeshi Yoshizaki,¹ Jill C. Milne,² Takeshi Imamura,¹ Simon Schenk,¹ Noriyuki Sonoda,¹ Jennie L. Babendure,¹ Juu-Chin Lu,¹ Jesse J. Smith,² Michael R. Jirousek,² and Jerrold M. Olefsky^1*

Division of Endocrinology and Metabolism, Department of Medicine, University of California at San Diego, 9500 Gilman Dr., La Jolla, California 92093,¹ Sirtris, 200 Technology Square, Suite 300, Cambridge, Massachusetts 02139²

Received 30 April 2008/ Returned for modification 10 June 2008/ Accepted 2 December 2008

SIRT1 is a prominent member of a family of NAD⁺-dependent enzymes and affects a variety of cellular functions ranging from gene silencing, regulation of the cell cycle and apoptosis, to energy homeostasis. In mature adipocytes, SIRT1 triggers lipolysis and loss of fat content. However, the potential effects of SIRT1 on insulin signaling pathways are poorly understood. To assess this, we used RNA interference to knock down SIRT1 in 3T3-L1 adipocytes. SIRT1 depletion inhibited insulin-stimulated glucose uptake and GLUT4 translocation. This was accompanied by increased phosphorylation of JNK and serine phosphorylation of insulin receptor substrate 1 (IRS-1), along with inhibition of insulin signaling steps, such as tyrosine phosphorylation of IRS-1, and phosphorylation of Akt and ERK. In contrast, treatment of cells with specific small molecule SIRT1 activators led to an increase in glucose uptake and insulin signaling as well as a decrease in serine phosphorylation of IRS-1. Moreover, gene expression profiles showed that SIRT1 expression was inversely related to inflammatory gene expression. Finally, we show that treatment of 3T3-L1 adipocytes with a SIRT1 activator attenuated tumor necrosis factor alpha-induced insulin resistance. Taken together, these data indicate that SIRT1 is a positive regulator of insulin signaling at least partially through the anti-inflammatory actions in 3T3-L1 adipocytes.

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* Corresponding author. Mailing address: Department of Medicine (0673), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92037-0673. Phone: (858) 534-6651. Fax: (858) 534-6653. E-mail: jolefsky{at}ucsd.edu

Published ahead of print on 22 December 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, March 2009, p. 1363-1374, Vol. 29, No. 5
0270-7306/09/$08.00+0     doi:10.1128/MCB.00705-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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