EGFR tyrosine kinase inhibitor (PD153035) improves glucose tolerance and insulin action in high-fat diet-fed mice.
In obesity, an increased macrophage infiltration in adipose tissue occurs, contributing to low-grade inflammation and insulin resistance. Epidermal growth factor receptor (EGFR) mediates both chemotaxis and proliferation in monocytes and macrophages. However, the role of EGFR inhibitors in this subclinical inflammation has not yet been investigated. We investigated, herein, in vivo efficacy and associated molecular mechanisms by which PD153035, an EGFR tyrosine kinase inhibitor, improved diabetes control and insulin action.



The effect of PD153035 was investigated on insulin sensitivity, insulin signaling, and c-Jun NH(2)-terminal kinase (JNK) and nuclear factor (NF)-kappaB activity in tissues of high-fat diet (HFD)-fed mice and also on infiltration and the activation state of adipose tissue macrophages (ATMs) in these mice.



PD153035 treatment for 1 day decreased the protein expression of inducible nitric oxide synthase, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 in the stroma vascular fraction, suggesting that this drug reduces the M1 proinflammatory state in ATMs, as an initial effect, in turn reducing the circulating levels of TNF-alpha and IL-6, and initiating an improvement in insulin signaling and sensitivity. After 14 days of drug administration, there was a marked improvement in glucose tolerance; a reduction in insulin resistance; a reduction in macrophage infiltration in adipose tissue and in TNF-alpha, IL-6, and free fatty acids; accompanied by an improvement in insulin signaling in liver, muscle, and adipose tissue; and also a decrease in insulin receptor substrate-1 Ser(307) phosphorylation in JNK and inhibitor of NF-kappaB kinase (IKKbeta) activation in these tissues.



Treatment with PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice.
Prada
Patricia O
PO
Department of Internal Medicine, State University of Campinas, Campinas, Brazil.
Ropelle
Eduardo R
ER
Mourão
Rosa H
RH
de Souza
Claudio T
CT
Pauli
Jose R
JR
Cintra
Dennys E
DE
Schenka
André
A
Rocco
Silvana A
SA
Rittner
Roberto
R
Franchini
Kleber G
KG
Vassallo
José
J
Velloso
Lício A
LA
Carvalheira
José B
JB
Saad
Mario J A
MJ
D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000187:drug effects / Q000378:metabolism; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D052242:Adiponectin; D001786:Blood Glucose; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; C526295:Irs1 protein, mouse; D020738:Leptin; D052002:NF-kappa B p50 Subunit; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; C073701:Nfkb1 protein, mouse; D052247:Nitric Oxide Synthase Type II; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline
Trends Immunol. 2004 Jan;25(1):4-7
14698276
Diabetes. 2009 Jan;58(1):104-15
18835938
Arch Ophthalmol. 2001 Mar;119(3):373-7
11231770
FASEB J. 2007 Apr;21(4):1153-63
17209127
Trends Cell Biol. 2002 Feb;12(2):65-71
11849969
Endocrinology. 2005 Mar;146(3):1576-87
15591151
Nature. 2002 Nov 21;420(6913):333-6
12447443
Leukemia. 2003 Sep;17(9):1713-21
12970769
Atherosclerosis. 2004 Sep;176(1):21-6
15306170
Am J Physiol Lung Cell Mol Physiol. 2002 May;282(5):L1040-8
11943669
Endocr Relat Cancer. 2005 Jun;12(2):471-82
15947117
Nat Rev Immunol. 2005 Aug;5(8):641-54
16056256
Nature. 2007 Jun 21;447(7147):959-65
17554340
J Biol Chem. 2003 Jul 4;278(27):24944-50
12714600
J Clin Invest. 2007 Jan;117(1):175-84
17200717
Cytokine. 2001 Dec 7;16(5):169-72
11814311
Diabetes. 2007 Aug;56(8):1986-98
17519423
J Lipid Res. 2005 Nov;46(11):2347-55
16150820
J Biol Chem. 2003 Jan 31;278(5):2896-902
12417588
Diabetes Care. 2006 Jul;29(7):1711
16801611
Endocrinology. 2004 Jan;145(1):281-93
14525909
Diabetes. 2005 Apr;54(4):959-67
15793233
J Clin Invest. 2003 Dec;112(12):1821-30
14679177
Science. 1994 Aug 19;265(5175):1093-5
8066447
N Engl J Med. 2005 Mar 10;352(10):1049-50
15758023
Trends Immunol. 2004 Dec;25(12):677-86
15530839
J Biol Chem. 2002 Jan 11;277(2):1531-7
11606564
J Biol Chem. 2000 Mar 24;275(12):9047-54
10722755
J Biol Chem. 2002 Dec 13;277(50):48115-21
12351658
Clin Cancer Res. 1997 Nov;3(11):2099-106
9815602
Science. 2001 Aug 31;293(5535):1673-7
11533494
J Physiol. 2006 Dec 15;577(Pt 3):997-1007
17008371
Nat Rev Mol Cell Biol. 2006 Feb;7(2):85-96
16493415
Diabetes. 2000 Jun;49(6):883-8
10866038
Lancet Oncol. 2009 May;10(5):522-7
19410197
Breast Cancer Res Treat. 2004 Jan;83(2):99-107
14997040
Acta Physiol Scand. 2005 Jan;183(1):13-30
15654917
J Clin Invest. 2006 Jul;116(7):1793-801
16823477
Ann Oncol. 2008 Apr;19(4):824-5
18326519
Exp Mol Med. 2007 Aug 31;39(4):524-34
17934341
J Clin Oncol. 2004 Nov 15;22(22):4653-5
15542819
Diabetes Care. 2004 Mar;27(3):813-23
14988310
J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Mar 25;817(2):297-302
15686998
Nat Rev Immunol. 2005 Dec;5(12):953-64
16322748
J Clin Invest. 2003 Dec;112(12):1796-808
14679176
Cell Signal. 2001 Feb;13(2):139-44
11257459
Blood. 2004 Jan 15;103(2):523-9
12969987