title: Effect of a p38 MAPK inhibitor on FFA-induced hepatic insulin resistance in vivo.
abstract: The mechanisms whereby prolonged plasma free fatty acids elevation, as found in obesity, causes hepatic insulin resistance are not fully clarified. We herein investigated whether inhibition of p38 mitogen-activated protein kinase (MAPK) prevented hepatic insulin resistance following prolonged lipid infusion. Chronically cannulated rats were subdivided into one of four intravenous (i.v.) treatments that lasted 48 h: Saline (5.5 μl min(-1)), Intralipid plus heparin (IH, 20% Intralipid+20 U ml(-1) heparin; 5.5 μl min(-1)), IH+p38 MAPK inhibitor (SB239063) and SB239063 alone. During the last 2 h of treatment, a hyperinsulinemic (5 mU kg(-1) min(-1)) euglycemic clamp together with [3-(3)H] glucose methodology was carried out to distinguish hepatic from peripheral insulin sensitivity. We found that SB239063 prevented IH-induced hepatic insulin resistance, but not peripheral insulin resistance. SB239063 also prevented IH-induced phosphorylation of activating transcription factor 2 (ATF2), a marker of p38 MAPK activity, in the liver. Moreover, in another lipid infusion model in mice, SB239063 prevented hepatic but not peripheral insulin resistance caused by 48 h combined ethyloleate plus ethylpalmitate infusion. Our results suggest that inhibition of p38 MAPK may be a useful strategy in alleviating hepatic insulin resistance in obesity-associated disorders.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Pereira
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors.forename: W Q
authors.initials: WQ
authors.lastname: Yu
authors.affiliation: Department of Health Sciences, Brock University, St Catherines, ON, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Moore
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.|Department of Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Health Sciences, Brock University, St Catherines, ON, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Tsiani
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.|Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Giacca
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004655:Emulsions / Q000008:administration & dosage / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D015309:Glucose Clamp Technique; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood; D010743:Phospholipids / Q000008:administration & dosage / Q000009:adverse effects; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013024:Soybean Oil / Q000008:administration & dosage / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; C497107:Atf2 protein, rat; D001786:Blood Glucose; D004655:Emulsions; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D007093:Imidazoles; D007328:Insulin; D010743:Phospholipids; D011743:Pyrimidines; C545823:soybean oil, phospholipid emulsion; D013024:Soybean Oil; D006493:Heparin; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063