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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 586/16/3825    most recent jphysiol.2008.157107v3 jphysiol.2008.157107v2 jphysiol.2008.157107v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Bisht, B. Articles by Dey, C. S. PubMed PubMed Citation Articles by Bisht, B. Articles by Dey, C. S. Related Collections Cellular

¹ Signal Transduction Research Laboratory, Department of Biotechnology
² Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has recently been implicated in the regulation of insulin resistance in vitro. However, its in vivo validation has not been attempted due to lethality of FAK knockout. Hence, to ascertain the role of FAK in the development of insulin resistance in vivo, we have down-regulated FAK expression by delivering FAK-specific small interfering RNA (siRNA) in mice using hydrodynamic tail vein injection. Here, we show for the first time that FAK silencing (57 ± 0.05% in muscle and 80 ± 0.08% in liver) exacerbates insulin signalling and causes hyperglycaemia (251.68 ± 8.1 mg dl^–1) and hyperinsulinaemia (3.48 ± 0.06 ng ml^–1) in vivo. FAK-silenced animals are less glucose tolerant and have physiological and biochemical parameters similar to that of high fat diet (HFD)-fed insulin-resistant animals. Phosphorylation and expression of insulin receptor substrate 1 (IRS-1) was attenuated by 40.2 ± 0.03% and 35.2 ± 0.6% in muscle and 52.3 ± 0.04% and 40.2 ± 0.03% in liver in FAK-silenced mice. Akt-Ser473-phosphorylation decreased in muscle and liver (50.3 ± 0.03% and 70.2 ± 0.02%, respectively) in FAK-silenced mice. This, in part, explains the mechanism of development of insulin resistance in FAK-silenced mice. The present study provides direct evidence that FAK is a crucial mediator of insulin resistance in vivo. Considering the lethality of FAK gene knockout the approach of this study will provide a new strategy for in vivo inhibition of FAK. Furthermore, the study should certainly motivate chemists to synthesize new chemical entities for FAK activation. This may shed light on new drug development against insulin resistance.

(Received 19 May 2008; accepted after revision 19 June 2008; first published online 26 June 2008)
Corresponding author C. S. Dey: Signal Transduction Research Laboratory, Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India. Email: csdey{at}niper.ac.in

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