EGFR Tyrosine Kinase Inhibitor (PD153035) Improves Glucose Tolerance and Insulin Action in High-Fat Diet–Fed Mice
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Figures
- FIG. 1.
Effects of acute or chronic PD153035 administration in fed mice. (A–C, upper panels). Representative blots show the tyrosine phosphorylation of EGFR of control mice, HFD mice, and HFDPD 1 and 14 days in liver (A), muscle (B), and adipose (C). Total protein expression of EGFR (A–C, lower panels). D: Body weight. E: Epididymal fat pad weight. F: Retroperitoneal fat pad weight. G: Mesenteric fat pad weight. H: Fasting plasma glucose. I: Glucose tolerance test. J: Serum insulin during glucose tolerance test. K: Glucose disappearance rate. L: Serum FFAs. Data are presented as means ± S.E.M from six to eight mice per group. *P < 0.05 vs. control group; #P < 0.01 vs. HFD. IB, immunoblot; IP, immunoprecipitate.
- FIG. 2.
Effects of PD153035 administration on insulin signaling in fed mice. Representative blots show tyrosine phosphorylation of IRβ in liver (A), muscle (B), and adipose (C) of control mice, HFD mice, and HFDPD during 14 days (upper panels). Total protein expression of IRβ (A–C, lower panels). Tyrosine phosphorylation of IRS-1 in liver (D), muscle (E), and retroperitoneal (F) of control mice, HFD mice, and HFDPD 14 days (upper panels). Total protein expression of IRS1 (D–F, lower panels). Serine phosphorylation of Akt in liver (G), muscle (H), and adipose (I) of control mice, HFD mice, and HFDPD 1 and 14 days (upper panels). Total protein expression of Akt (G–I, lower panels). Data are presented as means ± SE from six to eight mice per group. *P < 0.05 control vs. HFD group; #P < 0.05 HFPD 14 days vs. HFD. IB, immunoblot.
- FIG. 3.
Effects of PD153035 administration on modulators of insulin signaling. Representative blots show the expression of IKKβ phosphorylation in liver (A), muscle (B), and retroperitoneal (C) of control mice, HFD mice, and HFDPD 1 and 14 days (upper panels). Total protein expression of IKKβ (A–C, lower panels). IκBα in liver (D), muscle (E), and adipose (F) of control mice, HFD mice, and HFDPD 1 and 14 days. NFκB p50 activation was determined in nuclear extracts from liver (G), muscle (H), and adipose (I) tissue by ELISA. JNK phosphorylation in liver (J), muscle (K), and adipose (L) of control mice, HFD mice, and HFDPD 1 and 14 days (upper panels). Total protein expression of JNK (J–L, lower panels). c-Jun phosphorylation in liver (M), muscle (N), and adipose (O) of control mice, HFD mice, and HFDPD 1 and 14 days. IRS1 serine 307 phosphorylation in liver (P), muscle (Q), and adipose (R) of control mice, HFD mice, and HFPD 1 and 14 days (upper panels). Total protein expression of IRS-1 (P–R, lower panels). Data are presented as means ± SE from six mice per group, *P < 0.05 vs. control group and #P < 0.05 vs. HFD. IB, immunoblot.
- FIG. 4.
Effects of PD153035 on adipocyte morphology and activation and migration of macrophages in adipocyte tissue. A: Histological sections of retroperitoneal fat pads from control, HFD, and HFDPD after 1 or 14 days, 50-μm scale bar for all pictures. B: Quantification of adipocyte size. About 100 cells were measured in each group, and the average adipocyte was calculated. C: Representative immunohistochemical staining of WAT using the specific macrophage marker F4/80+. D: F4/80-positive cells (+cells/total cells) of all above groups. Data are presented as means ± SE from six mice per group, *P < 0.05 vs. control group and #P < 0.05 vs. HFD. E: Bar graph indicates the number of THP1 cells that migrate from the top to the bottom level of the Boyden blindwell chamber stimulated or not with chemotatic agent RANTES. *P < 0.05 vs. DMSO alone; #P < 0.05 vs. DMSO/RANTES. Values represent the average of five different assays. (A high-quality color digital representation of this figure is available in the online issue.)
- FIG. 5.
Effect of PD153035 on tissue protein levels of TNF-α, IL-6, and iNOS and arginase activity in adipocytes and SVF from retroperitoneal adipose tissue. Representative blots show the tissue levels of TNF-α, IL-6, iNOS, EGRF tyrosine phosphorylation, EGRF, Caveolin, and Cd68 protein expression in adipocytes (A–D) and TNF-α, IL-6, iNOS, EGRF tyrosine phosphorylation, EGRF, Cd68, and actin protein expression in the SVF (F–J). K: Arginase activity of adipocytes and SVF from control mice, HFD mice, and HFDPD 1 and 14 days. Serum levels of adiponectin (L), TNF-α (M), leptin (N), and IL-6 (O) and MCP-1 (P), MCP-2 (Q), and MCP-3 (R) protein expression were obtained using ELISA assay. Data are presented as means ± SE of six to eight mice per group. *P < 0.05 vs. control group; #P < 0.05 vs. HFD group.
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