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

234 Citations (Scopus)

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

Fingerprint

rosiglitazone
Peroxisome Proliferator-Activated Receptors
Metabolome
Metabolomics
Lipids
Metabolism
Tissue
Medical problems
Type 2 Diabetes Mellitus
Plasmas
Drug therapy
Cardiolipins
Plasma Exchange
Peroxisomes
Liver
Biosynthesis
Biomarkers
Nutrition
Metabolites
Dietary Supplements

Keywords

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

ASJC Scopus subject areas

  • Endocrinology

Cite this

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

Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone. / Watkins, Steven M.; Reifsnyder, Peter R.; Pan, Huei Ju; Bruce German, J.; Leiter, Edward H.

In: Journal of Lipid Research, Vol. 43, No. 11, 01.11.2002, p. 1809-1817.

Research output: Contribution to journalArticle

Watkins, SM, Reifsnyder, PR, Pan, HJ, Bruce German, J & Leiter, EH 2002, 'Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone', Journal of Lipid Research, vol. 43, no. 11, pp. 1809-1817. https://doi.org/10.1194/jlr.M200169-JLR200
Watkins SM, Reifsnyder PR, Pan HJ, Bruce German J, Leiter EH. Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone. Journal of Lipid Research. 2002 Nov 1;43(11):1809-1817. https://doi.org/10.1194/jlr.M200169-JLR200
Watkins, Steven M. ; Reifsnyder, Peter R. ; Pan, Huei Ju ; Bruce German, J. ; Leiter, Edward H. / Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone. In: Journal of Lipid Research. 2002 ; Vol. 43, No. 11. pp. 1809-1817.
@article{ea0fd699502149fb995f0aa50526a628,
title = "Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone",
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.",
keywords = "Diabetes, Lipid metabolism, Metabolomics, Mouse, Peroxisome proliferator-activated receptor γ, Steatosis",
author = "Watkins, {Steven M.} and Reifsnyder, {Peter R.} and Pan, {Huei Ju} and {Bruce German}, J. and Leiter, {Edward H.}",
year = "2002",
month = "11",
day = "1",
doi = "10.1194/jlr.M200169-JLR200",
language = "English (US)",
volume = "43",
pages = "1809--1817",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "11",

}

TY - JOUR

T1 - Lipid metabolome-wide effects of the PPARγ agonist rosiglitazone

AU - Watkins, Steven M.

AU - Reifsnyder, Peter R.

AU - Pan, Huei Ju

AU - Bruce German, J.

AU - Leiter, Edward H.

PY - 2002/11/1

Y1 - 2002/11/1

N2 - 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.

AB - 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.

KW - Diabetes

KW - Lipid metabolism

KW - Metabolomics

KW - Mouse

KW - Peroxisome proliferator-activated receptor γ

KW - Steatosis

UR - http://www.scopus.com/inward/record.url?scp=0036846241&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036846241&partnerID=8YFLogxK

U2 - 10.1194/jlr.M200169-JLR200

DO - 10.1194/jlr.M200169-JLR200

M3 - Article

C2 - 12401879

AN - SCOPUS:0036846241

VL - 43

SP - 1809

EP - 1817

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 11

ER -