Insulin Signaling and Gene Regulation in Transfected Adipose Cells

Quon, M J.

Abstract

Our laboratory is interested in elucidating the molecular basis for the relationship between hypertension, insulin resistance, and obesity. In classical insulin target tissues such as muscle and fat, insulin stimulates glucose uptake primarily by causing translocation of the insulin responsive glucose transporter GLUT4 from an intracellular pool to the cell surface. Decreased sensitivity to this action of insulin (i.e., insulin resistance) plays a major role in the pathogenesis of diabetes and has been strongly correlated with hypertension and obesity. To understand the mechanisms involved in insulin-stimualted glucose transport under both normal and pathological conditions, we have developed a novel method for transient transfection of DNA into rat adipose cells in primary culture. This allows us to dissect the insulin signal transduction pathways related to GLUT4 translocation in a physiologically relevant insulin target cell. In addition, our adipose cell transfection system is useful for studying the regulation of adipose cell specific genes. We have established a collaboration with Marc Reitman's laboratory in NIDDK to study the promoter of the recently cloned ob gene (leptin, the ob gene product, is a putative satiety hormone).

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Heart, Lung, and Blood Institute (NHLBI)
• Type: Intramural Research (Z01)
• Project #: 1Z01HL003608-01
• Application #: 5203557
• Support Year: 1
• Fiscal Year: 1995

Institution

• Name: National Heart, Lung, and Blood Institute
• Country: United States

Publications

Esposito, D L; Li, Y; Cama, A et al. (2001) Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells. Endocrinology 142:2833-40

Ravichandran, L V; Esposito, D L; Chen, J et al. (2001) Protein kinase C-zeta phosphorylates insulin receptor substrate-1 and impairs its ability to activate phosphatidylinositol 3-kinase in response to insulin. J Biol Chem 276:3543-9

Bandyopadhyay, G; Sajan, M P; Kanoh, Y et al. (2001) Glucose activates protein kinase C-zeta /lambda through proline-rich tyrosine kinase-2, extracellular signal-regulated kinase, and phospholipase D: a novel mechanism for activating glucose transporter translocation. J Biol Chem 276:35537-45

Bandyopadhyay, G; Sajan, M P; Kanoh, Y et al. (2000) Glucose activates mitogen-activated protein kinase (extracellular signal-regulated kinase) through proline-rich tyrosine kinase-2 and the Glut1 glucose transporter. J Biol Chem 275:40817-26

Ahmad, F; Cong, L N; Stenson Holst, L et al. (2000) Cyclic nucleotide phosphodiesterase 3B is a downstream target of protein kinase B and may be involved in regulation of effects of protein kinase B on thymidine incorporation in FDCP2 cells. J Immunol 164:4678-88

Wanant, S; Quon, M J (2000) Insulin receptor binding kinetics: modeling and simulation studies. J Theor Biol 205:355-64

Chen, H; Cong, L N; Li, Y et al. (1999) A phosphotyrosyl mimetic peptide reverses impairment of insulin-stimulated translocation of GLUT4 caused by overexpression of PTP1B in rat adipose cells. Biochemistry 38:384-9

Nystrom, F H; Chen, H; Cong, L N et al. (1999) Caveolin-1 interacts with the insulin receptor and can differentially modulate insulin signaling in transfected Cos-7 cells and rat adipose cells. Mol Endocrinol 13:2013-24

Cong, L N; Chen, H; Li, Y et al. (1999) Overexpression of protein tyrosine phosphatase-alpha (PTP-alpha) but not PTP-kappa inhibits translocation of GLUT4 in rat adipose cells. Biochem Biophys Res Commun 255:200-7

Zhao, W; Chen, H; Xu, H et al. (1999) Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274:34893-902