title: EGFR tyrosine kinase inhibitor (PD153035) improves glucose tolerance and insulin action in high-fat diet-fed mice.
abstract: 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.
authors.affiliation: Department of Internal Medicine, State University of Campinas, Campinas, Brazil.
authors.forename: Patricia O
authors.initials: PO
authors.lastname: Prada
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Ropelle
authors.forename: Rosa H
authors.initials: RH
authors.lastname: Mourão
authors.forename: Claudio T
authors.initials: CT
authors.lastname: de Souza
authors.forename: Jose R
authors.initials: JR
authors.lastname: Pauli
authors.forename: Dennys E
authors.initials: DE
authors.lastname: Cintra
authors.forename: André
authors.initials: A
authors.lastname: Schenka
authors.forename: Silvana A
authors.initials: SA
authors.lastname: Rocco
authors.forename: Roberto
authors.initials: R
authors.lastname: Rittner
authors.forename: Kleber G
authors.initials: KG
authors.lastname: Franchini
authors.forename: José
authors.initials: J
authors.lastname: Vassallo
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
authors.forename: José B
authors.initials: JB
authors.lastname: Carvalheira
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Saad
mesh_terms: 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
chemical_list: 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
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