Hepatocyte growth factor induces glucose uptake in 3T3-L1 adipocytes through A Gab1/phosphatidylinositol 3-kinase/Glut4 pathway.
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 alpha 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 alpha-treated adipocytes.
Bertola
Adeline
A
INSERM, U 568, F-06107 Nice, France, Université de Nice Sophia-Antipolis, Faculté de Médecine, F-06107, Nice, France.
Bonnafous
Stéphanie
S
Cormont
Mireille
M
Anty
Rodolphe
R
Tanti
Jean-François
JF
Tran
Albert
A
Le Marchand-Brustel
Yannick
Y
Gual
Philippe
P
D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D051379:Mice; D008820:Mice, Obese; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D005947:Glucose; D051275:Glucose Transporter Type 4; D017228:Hepatocyte Growth Factor; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; C490897:Gab1 protein, mouse; C526292:IRS1 protein, human; C526295:Irs1 protein, mouse; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; C089946:2,4-thiazolidinedione