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Published on: January 4, 2018
LPS-induced biomarkers in mice: a potential model for identifying insulin sensitizers
Celia P Briscoe1, David Looper, Phong Tran
1Diabetes Biology Department, Pfizer Incorporated, PGRD-La Jolla, 10724 Science Center Drive, San Diego, CA 92121, USA. Celia.Jenkinson@earthlink.net
Abstract:
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.
Insights
Lipopolysaccharide (LPS) triggers inflammation and insulin resistance by increasing inflammatory cytokines and activating c-Jun N-terminal kinase (JNK) and S6 kinase (S6K) pathways. This study establishes LPS as a model for developing new insulin resistance therapies.
Area of Science:
- Biomedical research
- Inflammation and immunology
- Metabolic disorders
Background:
- Nutrient overload and inflammation contribute to insulin resistance.
- c-Jun N-terminal kinase (JNK) and S6 kinase (S6K) are therapeutic targets for insulin resistance.
Purpose of the Study:
- To investigate how lipopolysaccharide (LPS)-induced inflammation modulates pathways linked to insulin resistance.
- To characterize LPS-induced changes in key biomarkers.
Main Methods:
- Administration of varying doses of LPS (0.06-4 mg/kg) to C57BL/6 mice.
- Measurement of plasma cytokine levels (TNFalpha, IL-12p40, IL-6, MCP-1).
- Assessment of JNK activity (phosphorylated c-Jun) in fat and S6K activity (phosphorylated S6 ribosomal protein) in liver.
Main Results:
- LPS administration increased plasma levels of TNFalpha, IL-12p40, IL-6, and MCP-1.
- LPS significantly increased JNK activity in adipose tissue.
- LPS induced S6K activity in the liver and elevated plasma osteopontin levels, a cytokine implicated in insulin resistance.
Conclusions:
- LPS induces a pro-inflammatory response involving key kinases (JNK, S6K) and cytokines.
- Elevated osteopontin is a novel finding linked to LPS-induced inflammation and insulin resistance.
- LPS administration provides a robust in vivo model for evaluating therapies targeting multiple insulin resistance pathways.
