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. 2012 Apr 30;4(4):32.
doi: 10.1186/gm331.

Applications of metabolomics for understanding the action of peroxisome proliferator-activated receptors (PPARs) in diabetes, obesity and cancer

Zsuzsanna Ament  1 , Mojgan Masoodi, Julian L Griffin
Affiliations

Applications of metabolomics for understanding the action of peroxisome proliferator-activated receptors (PPARs) in diabetes, obesity and cancer

Zsuzsanna Ament et al. Genome Med. .

Abstract

The peroxisome proliferator-activated receptors (PPARs) are a set of three nuclear hormone receptors that together play a key role in regulating metabolism, particularly the switch between the fed and fasted state and the metabolic pathways involving fatty-acid oxidation and lipid metabolism. In addition, they have a number of important developmental and regulatory roles outside metabolism. The PPARs are also potent targets for treating type II diabetes, dyslipidemia and obesity, although a number of individual agonists have also been linked to unwanted side effects, and there is a complex relationship between the PPARs and the development of cancer. This review examines the part that metabolomics, including lipidomics, has played in elucidating the roles PPARs have in regulating systemic metabolism, as well as their role in aspects of drug-induced cancer and xenobiotic metabolism. These studies have defined the role PPARδ plays in regulating fatty-acid oxidation in adipose tissue and the interaction between aging and PPARα in the liver. The potential translational benefits of these approaches include widening the role of PPAR agonists and improved monitoring of drug efficacy.

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Figures

Figure 1
Figure 1
A schematic diagram illustrating the cross-talk of the three PPAR receptors and the metabolic pathways they interact with. For each PPAR, the initial step involves the receptor binding a ligand to activate it. Then, the retinoid × receptor (RXR), a nuclear receptor activated by 9-cis retinoic acid, heterodimerizes with a PPAR prior to the subsequent binding of the complex with DNA. Key: NSAID, non-steroidal anti-inflammatory drug; TZD, thiazolidinedione, a class of drugs that bind to PPARγ and have insulin-sensitizing properties; VLDL, very low density lipoprotein (used to transport lipids in the blood).
Figure 2
Figure 2
Metabolic changes in the PPARα-null mouse. (a) 1H-NMR spectra showing the difference in glucose and glycogen concentration between 3 and 13 months for liver tissue extracts from PPARα-null mice. Each spectrum is the average of the five spectra obtained from all animals at that age. Key: red, 3 months; blue, 5 months; black, 11 months; green, 13 months. (b) Principal components analysis (PCA) plot showing the clustering of 3-month (open circles), 5-month (open diamonds), 7-month (stars), 9-month (open triangles), 11-month (black squares) and 13-month (crosses) liver tissue across principal component 1. (c) Partial least squares plot regressing age of animal (y-axis) against the metabolic profile of the liver tissue (x-axis) in control mice as measured by 1H NMR spectroscopy. PPARα-null mice were then mapped on to the same model. Error bars indicate standard error. Reproduced from [20] with permission.
Figure 3
Figure 3
Stable Isotope flux analysis of PPARδ-agonist-treated 3T3-L1 adipocytes. (a) Graphs showing the M+1/M isotope ratio 13C enrichment of lactate, glutamate and succinate analyzed by GC-MS of the aqueous fraction and M+1/M isotope ratio 13C enrichment of palmitic acid analyzed by GC-MS of the organic fraction from control (n = 6) and PPARδ-agonist-dosed (n = 6) 3T3-L1 cells incubated with 1-13C glucose. *P < 0.05, **P < 0.01. The metabolites have been mapped to the glycolysis and tricarboxylic acid cycle metabolic pathways. Up arrow indicates a metabolite increased, and down arrow indicates a metabolite decreased in 13C enrichment by PPARδ activation. (b) Graphs showing the M+1/M isotope ratio 13C enrichment of malate, glutamate, fumarate and succinate analyzed by GC-MS of the aqueous fraction and enrichment of arachidic acid, stearic acid, palmitoleic acid, myristic acid and lauric acid analyzed by GC-MS of the organic fraction from control (n = 6) and PPARδ-agonist-dosed (n = 6) 3T3-L1 cells incubated with U-13C palmitate. *P < 0.05, **P < 0.01,***P < 0.005. Up arrow indicates a metabolite increased, and down arrow indicates a metabolite decreased in 13C enrichment by PPARδ activation. Parent ions were used to calculate the ion ratio. Reproduced from [30] with permission.
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