title: Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats.
abstract: OBJECTIVE
  To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats.
  
  
  METHODS
  For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp.
  
  
  RESULTS
  Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP.
  
  
  CONCLUSIONS
  Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo.
authors.affiliation: Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States of America; Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States of America; The Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, 78229, United States of America.
authors.forename: Hanyu
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Internal Medicine, The University of South Florida, Tampa, FL 33620, United States of America; James A Hayley Veterans Medical Center, Tampa, FL, 33612, United States of America.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.affiliation: Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States of America; Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States of America.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States of America; Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States of America; The Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, 78229, United States of America.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.affiliation: Department of Internal Medicine, The University of South Florida, Tampa, FL 33620, United States of America; James A Hayley Veterans Medical Center, Tampa, FL, 33612, United States of America.
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Hussey
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008055:Lipids / Q000008:administration & dosage / Q000009:adverse effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C404742:E5564; D008050:Lipid A; D008055:Lipids; D013449:Sulfonamides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D005947:Glucose