LPS-induced biomarkers in mice: a potential model for identifying insulin sensitizers.
The contribution of nutrient overload and associated inflammation to insulin resistance has highlighted several therapeutic targets including c-Jun N-terminal kinase (JNK) and S6 kinase (S6K). To investigate how a lipopolysaccharide (LPS)-mediated inflammatory response may modulate pathways implicated in insulin resistance, we characterized the LPS-induced changes in key biomarkers. Administration of 0.06-4 mg/kg LPS to C57BL/6 mice stimulated increases in plasma levels of TNFalpha, IL-12p40, IL-6 and MCP-1 and in JNK activity as measured by phosphorylated c-Jun in fat. For the first time, we show that LPS induces S6K activity by up to 6.1-fold, as measured by the phosphorylation of S6 ribosomal protein in liver, and increases by up to 1.8-fold, plasma levels of the novel pro-inflammatory cytokine osteopontin which is implicated in the pathogenesis of insulin resistance. These novel findings suggest that LPS administration may form the basis of an acute in vivo pharmacodynamic model for therapies targeting multiple pathways implicated in insulin resistance.
Briscoe
Celia P
CP
Diabetes Biology Department, Pfizer Incorporated, PGRD-La Jolla, 10724 Science Center Drive, San Diego, CA 92121, USA. Celia.Jenkinson@earthlink.net
Looper
David
D
Tran
Phong
P
Herrera
Jocelyn
J
McDonnell
Scott R
SR
Bhat
B Ganesh
BG
D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053495:Osteopontin / Q000097:blood; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism
D015415:Biomarkers; D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin; D008070:Lipopolysaccharides; D053495:Osteopontin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases