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J. Biol. Chem., Vol. 282, Issue 14, 10325-10332, April 6, 2007

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Hepatocyte Growth Factor Induces Glucose Uptake in 3T3-L1 Adipocytes through A Gab1/Phosphatidylinositol 3-Kinase/Glut4 Pathway^*

Adeline Bertola^¶1, Stéphanie Bonnafous², Mireille Cormont, Rodolphe Anty^¶, Jean-François Tanti, Albert Tran^¶, Yannick Le Marchand-Brustel^¶3, and Philippe Gual^¶34

From the INSERM, U 568, F-06107 Nice, France, Université de Nice Sophia-Antipolis, Faculté de Médecine, F-06107, Nice, France, and ^¶Fédération d'Hépatologie, CHU de Nice F-06202, France

Adipose tissue is a source of hepatocyte growth factor (HGF), and circulating HGF levels have been associated with elevated body mass index in human. However, the effects of HGF on adipocyte functions have not yet been investigated. We show here that in 3T3-L1 adipocytes HGF stimulates the phosphatidylinositol (PI) 3-kinase-dependent protein kinase B (PKB) activity, AS160 phosphorylation, Glut4 translocation, and consequently, glucose uptake. The initial steps involved in HGF- and insulin-induced glucose uptake are different. HGF enhanced the tyrosine phosphorylation of Gab1, leading to the recruitment of the p85-regulated subunit of PI 3-kinase, whereas p85 was exclusively recruited by IRS1 in response to insulin. In adipocytes rendered insulin-resistant by a long-lasting tumor necrosis factor treatment, the protein level of Gab1 was strongly decreased, and HGF-stimulated PKB activation and glucose uptake were also altered. Moreover, treatment of 3T3-L1 adipocytes with thiazolidinedione, an anti-diabetic drug, enhanced the expression of both HGF and its receptor. These data provide the first evidence that in vitro HGF promotes glucose uptake through a Gab1/PI 3-kinase/PKB/AS160 pathway which was altered in tumor necrosis factor -treated adipocytes.

Received for publication, December 22, 2006 , and in revised form, February 5, 2007.

^* This work was supported by grants from the INSERM (France), the University of Nice, the Programme Hospitalier de Recherche Clinique (CHU of Nice), the Comité Doyen Jean Lépine (Nice, France), French Research Ministry Grants ACI JC5327 and ANR-05-PCOD-025-02 (to P. G.), and a ROCHE-AFERO grant (to P. G.). This work is part of the project "Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome", which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005-018734). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Programme Hospitalier de Recherche Clinique (CHU of Nice).

² Supported by ANR-05-PCOD-025-02.

³ Recipient of an Interface Grant from CHU of Nice.

⁴ To whom correspondence should be addressed: INSERM U 568, Facultéde médecine, avenue de Valombrose, 06107 Nice Cedex 02, France. Tel.: 33-4-93-37-76-30; Fax: 33-4-93-37-77-01; E-mail: gual{at}unice.fr.

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