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Suppression of PPAR- attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes

¹Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California; and ²Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California

Submitted 19 December 2006 ; accepted in final form 22 March 2007

Peroxisome proliferator-activated receptor- (PPAR-) plays a critical role in regulating insulin sensitivity and glucose homeostasis. In this study, we identified highly efficient small interfering RNA (siRNA) sequences and used lentiviral short hairpin RNA and electroporation of siRNAs to deplete PPAR- from 3T3-L1 adipocytes to elucidate its role in adipogenesis and insulin signaling. We show that PPAR- knockdown prevented adipocyte differentiation but was not required for maintenance of the adipocyte differentiation state after the cells had undergone adipogenesis. We further demonstrate that PPAR- suppression reduced insulin-stimulated glucose uptake without affecting the early insulin signaling steps in the adipocytes. Using dual siRNA strategies, we show that this effect of PPAR- deletion was mediated by both GLUT4 and GLUT1. Interestingly, PPAR--depleted cells displayed enhanced inflammatory responses to TNF- stimulation, consistent with a chronic anti-inflammatory effect of endogenous PPAR-. In summary, 1) PPAR- is essential for the process of adipocyte differentiation but is less necessary for maintenance of the differentiated state, 2) PPAR- supports normal insulin-stimulated glucose transport, and 3) endogenous PPAR- may play a role in suppression of the inflammatory pathway in 3T3-L1 cells.

small interfering RNA; lentivirus; peroxisome proliferator activated-receptor-

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