Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone

Steven M. Watkins, Peter R. Reifsnyder, Huei Ju Pan, J. Bruce German, Edward H. Leiter

Research output: Contribution to journalArticle

238 Scopus citations

Abstract

Successful therapy for chronic diseases must normalize a targeted aspect of metabolism without disrupting the regulation of other metabolic pathways essential for maintaining health. Use of a limited number of single molecule surrogates for disease, or biomarkers, to monitor the efficacy of a therapy may fail to predict undesirable side effects. In this study, a comprehensive metabolomic assessment of lipid metabolites was employed to determine the specific effects of the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone on structural lipid metabolism in a new mouse model of Type 2 diabetes. Dietary supplementation with rosiglitazone (200 mg/kg diet) suppressed Type 2 diabetes in obese (NZO × NON)F1 male mice, but chronic treatment markedly exacerbated hepatic steatosis. The metabolomic data revealed that rosiglitazone i) induced hypolipidemia (by dysregulating liver-plasma lipid exchange), ii) induced de novo fatty acid synthesis, iii) decreased the biosynthesis of lipids within the peroxisome, iv) substantially altered free fatty acid and cardiolipin metabolism in heart, and v) elicited an unusual accumulation of polyunsaturated fatty acids within adipose tissue. These observations suggest that the phenotypes induced by rosiglitazone are mediated by multiple tissue-specific metabolic variables. Because many of the effects of rosiglitazone on tissue metabolism were reflected in the plasma lipid metabolome, metabolomics has excellent potential for developing clinical assessments of metabolic response to drug therapy.

Original languageEnglish (US)
Pages (from-to)1809-1817
Number of pages9
JournalJournal of Lipid Research
Volume43
Issue number11
DOIs
StatePublished - Nov 1 2002

Keywords

  • Diabetes
  • Lipid metabolism
  • Metabolomics
  • Mouse
  • Peroxisome proliferator-activated receptor γ
  • Steatosis

ASJC Scopus subject areas

  • Endocrinology

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    Watkins, S. M., Reifsnyder, P. R., Pan, H. J., Bruce German, J., & Leiter, E. H. (2002). Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone. Journal of Lipid Research, 43(11), 1809-1817. https://doi.org/10.1194/jlr.M200169-JLR200