Activation of Mitogen-activated Protein Kinase and Phosphatidylinositol 3′-Kinase Is Not Sufficient for the Hormonal Stimulation of Glucose Uptake, Lipogenesis, or Glycogen Synthesis in 3T3-L1 Adipocytes

Abstract

The precise mechanism by which insulin regulates glucose metabolism is not fully understood. However, it is known that insulin activates two enzymes, phosphatidylinositol 3'-kinase (PI 3'-K) and mitogen-activated protein kinase (MAPK), which may be involved in stimulating the metabolic effects of insulin. The role of these enzymes in glucose metabolism was examined by comparing the effects of insulin, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) in 3T3-L1 adipocytes. Treatment of the cells with PDGF or EGF for 5 min increased the MAPK activity 3-5-fold, while insulin treatment produced a 2.5-fold increase. The MAPK activity remained elevated for 1 h after either PDGF or insulin treatment. PDGF and insulin, but not EGF, caused a transient increase in the amount PI 3'-K activity coprecipitated with tyrosine phosphorylated proteins. Although PDGF and insulin caused a similar increase in the activities of these two enzymes, only insulin caused substantial increases in glucose utilization. Insulin increased the transport of glucose and the synthesis of lipid 4- and 17-fold, respectively, while PDGF did not affect these processes significantly. Glycogen synthesis was increased 15-fold in response to insulin and only 3-fold in response to PDGF. Thus, the activation of MAPK and PI 3'-K are not sufficient for the complete stimulation of glucose transport, lipid synthesis, or glycogen synthesis by hormones in 3T3-L1 adipocytes, suggesting a requirement for other signaling mechanisms that may be uniquely responsive to insulin.

Increased mitogen-activated protein kinase expression and activity in white adipose tissue of ventromedial hypothalamus-lesioned rats

“…Similar increases in protein content have been observed previously in WAT of obese VMH [3,12,27] and in Zucker rats [32]. Although the potential role of MAPK in the regulation of protein synthesis is controversial [31,[33][34][35], it cannot be excluded that the overexpression of MAPK in WAT of VMH rats could play a role in the general increase in protein content in adipocytes of obese rats. On the other hand, it has been shown in NIH3T3 fibroblasts that ERK-2 activation in vivo correlated with enhanced activation of RNA polymerase II [36,37].…”

Elevated urokinase-type plasminogen activator receptor expression in a colon cancer cell line is due to a constitutively activated extracellular signal-regulated kinase-1-dependent signaling cascade

“…However, the mechanism(s) by which the u-PAR gene is overexpressed is unclear at the present time. Since phorbol ester and a variety of growth factors including EGF, FGF, and vEGF, which up-regulate u-PAR synthesis, stimulate ERK activity (Zohn et al, 1995;Wiese et al, 1995;Bogoyevitch et al, 1994;Campbell et al, 1995;Jones et al, 1994;Lund et al, 1995), we undertook a study to determine the role of these MAPKs in regulating u-PAR expression in two cultured colon cancer cell lines. Several observations suggested a role for an ERK1-dependent signaling cascade in the regulation of u-PAR expression.…”

Regulation of Peroxisome Proliferator-activated Receptor γ Activity by Mitogen-activated Protein Kinase

“…Additional studies on adipocyte function show that although insulin activates MAP kinase in 3T3-L1 adipocytes, insulin-dependent metabolic responses such as glucose uptake, glycogen synthesis, and lipogenesis are unaffected by the inhibition of MAP kinase with the MEK inhibitor PD98059 (29,30). In addition, the MEK inhibitor does not prevent or delay 3T3-L1 adipocyte differentiation (data not shown).…”

“…Moreover, recently Hu et al (28) demonstrated that the ectopic expression of a mutant PPAR␥2 (a serine to alanine mutation at position 112 in PPAR␥2, which is equivalent to Ser 82 of PPAR␥1) enhanced sensitivity to ligand-induced adipogenesis. These results strongly support the conclusion of the present paper.Additional studies on adipocyte function show that although insulin activates MAP kinase in 3T3-L1 adipocytes, insulin-dependent metabolic responses such as glucose uptake, glycogen synthesis, and lipogenesis are unaffected by the inhibition of MAP kinase with the MEK inhibitor PD98059 (29,30). In addition, the MEK inhibitor does not prevent or delay 3T3-L1 adipocyte differentiation (data not shown).…”