Increased adipose tissue expression of Grb14 in several models of insulin resistance.
Grb14 is an effector of insulin signaling, which directly inhibits insulin receptor catalytic activity in vitro. Here, we investigated whether the expression of Grb14 and its binding partner ZIP (PKC zeta interacting protein) is regulated during insulin resistance in type 2 diabetic rodents and humans. Grb14 expression was increased in adipose tissue of both ob/ob mice and Goto-Kakizaki (GK) rats, whereas there was no difference in liver. An increase was also observed in subcutaneous adipose tissue of type 2 diabetic subjects when compared with controls. ZIP expression was increased in adipose tissue of ob/ob mice and type 2 diabetic patients, but it did not vary in GK rats. Hormonal regulation of Grb14 and ZIP expression was then investigated in 3T3-F442A adipocytes. In this model, insulin stimulated Grb14 expression, while TNF-alpha increased ZIP expression. Moreover, the insulin-sensitizing drugs thiazolidinediones (TZDs) decreased Grb14 expression in 3T3-F442A adipocytes. Finally, we investigated the dynamic regulation of Grb14 expression in ob/ob mice in several conditions improving their insulin sensitivity. Prolonged fasting and treatment with metformin significantly decreased Grb14 expression in peri-epidydimal adipose tissue, while there was only a trend to a diminution after TZD treatment. Taken together, these results suggest that the regulation of Grb14 expression in adipose tissue may play a physiological role in insulin sensitivity.
Cariou
Bertrand
B
Département d'Endocrinologie, Institut Cochin INSERM U 567-CNRS UMR 8104-Université René Descartes, Paris, France.
Capitaine
Nadège
N
Le Marcis
Véronique
V
Vega
Nathalie
N
Béréziat
Véronique
V
Kergoat
Micheline
M
Laville
Martine
M
Girard
Jean
J
Vidal
Hubert
H
Burnol
Anne-Françoise
AF
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005215:Fasting; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C490977:Grb14 protein, mouse; C490976:Grb14 protein, rat; D007328:Insulin; D011506:Proteins; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008687:Metformin; C089946:2,4-thiazolidinedione