Modulation of insulin activities by leptin.
Leptin mediates its effects on food intake through the hypothalamic form of its receptor OB-R. Variants of OB-R are found in other tissues, but their function is unknown. Here, an OB-R variant was found in human hepatic cells. Exposure of these cells to leptin, at concentrations comparable with those present in obese individuals, caused attenuation of several insulin-induced activities, including tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1, and down-regulation of gluconeogenesis. In contrast, leptin increased the activity of IRS-1-associated phosphatidylinositol 3-kinase. These in vitro studies raise the possibility that leptin modulates insulin activities in obese individuals.
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. lvrub@weizmann.weizmann.ac.il
B
B
Cohen
D
D
Novick
M
M
Rubinstein
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists; D055504:Insulin Receptor Substrate Proteins; D020738:Leptin; D008099:Liver / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology*; D011972:Receptor, Insulin / Q000378:metabolism; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D066246:ErbB Receptors; D051380:GRB2 Adaptor Protein; D005947:Glucose; D007328:Insulin; D007329:Insulin Antagonists; D055504:Insulin Receptor Substrate Proteins; D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D019000:Phosphotyrosine; D011506:Proteins; D011972:Receptor, Insulin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C495948:GRB2 protein, human; C526292:IRS1 protein, human; C515448:LEPR protein, human