PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption.
- Authors
- Ferguson, Laura B; Most, Dana; Blednov, Yuri A; Harris, R Adron
- Year
- 2014
- Journal
- Neuropharmacology
- PMID
- 25036611
- DOI
- 10.1016/j.neuropharm.2014.06.024
- PMCID
- PMC4188800
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Although prescribed for dyslipidemia and type-II diabetes, PPAR agonists also possess anti-addictive characteristics. PPAR agonists decrease ethanol consumption and reduce withdrawal severity and susceptibility to stress-induced relapse in rodents. However, the cellular and molecular mechanisms facilitating these properties have yet to be investigated. We tested three PPAR agonists in a continuous access two-bottle choice (2BC) drinking paradigm and found that tesaglitazar (PPARα/γ; 1.5 mg/kg) and fenofibrate (PPARα; 150 mg/kg) decreased ethanol consumption in male C57BL/6J mice while bezafibrate (PPARα/γ/β; 75 mg/kg) did not. We hypothesized that changes in brain gene expression following fenofibrate and tesaglitazar treatment lead to reduced ethanol drinking. We studied unbiased genomic profiles in areas of the brain known to be important for ethanol dependence, the prefrontal cortex (PFC) and amygdala, and also profiled gene expression in liver. Genomic profiles from the non-effective bezafibrate treatment were used to filter out genes not associated with ethanol consumption. Because PPAR agonists are anti-inflammatory, they would be expected to target microglia and astrocytes. Surprisingly, PPAR agonists produced a strong neuronal signature in mouse brain, and fenofibrate and tesaglitazar (but not bezafibrate) targeted a subset of GABAergic interneurons in the amygdala. Weighted gene co-expression network analysis (WGCNA) revealed co-expression of treatment-significant genes. Functional annotation of these gene networks suggested that PPAR agonists might act via neuropeptide and dopaminergic signaling pathways in the amygdala. Our results reveal gene targets through which PPAR agonists can affect alcohol consumption behavior.
PPAR agonists decrease ethanol consumption and preference without changing water intakeEthanol consumption in grams per kilogram of mouse body weight over a 24-hour period averaged for days 5 and 6. We calculated preference as the amount of ethanol consumed divided by the total amount of fluids consumed per day (a value > 50% indicates a preference for ethanol). Values are expressed as mean ± S.E.M. N = 8 mice in each group: bezafibrate (pan-PPAR agonist), tesaglitazar (dual PPARα and γ agonist) and fenofibrate (PPARα agonist). Overall fluid intake is shown on the far right. Statistical analysis was performed by a two-way ANOVA with repeated measurements and Bonferroni post hoc test. *** p-value < 0.0001 and ** p-value < 0.001.
PPAR agonists alter gene expression in the amygdala and PFC and produce a strong neuronal signature in the amygdalaThe number of genes up- and down-regulated by fenofibrate (feno) (N=9), tesaglitazar (tesa) (N= 9 – 10) and bezafibrate (beza) (N=9 –10) as compared to saline control (N=9 – 10) in the amygdala (A) and PFC (B). The numbers above and below the bars represent numbers of up- and down-regulated genes, respectively. We used lists from previously published data containing genes that are preferentially expressed in certain cell types to examine the cell-type specificity of PPAR agonists and tested for enrichment of genes that are preferentially expressed in astrocytes, microglia, neurons, oligodendrocytes (oligos), glutamatergic neurons and GABAergic neurons. The boxes indicate the cell-types that are overrepresented (hypergeometric p-value < 0.05) in the corresponding gene-set.
Genes implicated in alcohol consumption (from mutant mouse studies) that are in PPAR agonist-regulated genesets in the amygdala and PFCThe diagrams show the alcohol-related genes regulated by PPAR agonists in the amygdala (left) and PFC (right). Genes were determined to be alcohol-related if mice lacking or over-expressing that gene showed differences in alcohol consumption compared to wild-type mice. Genes regulated by fenofibrate (feno) only, tesaglitazar (tesa) only, and both feno and tesa are shown on the left, right, and center of each diagram, respectively, excluding those genes also regulated by the ineffective bezafibrate treatment.
Comparison of the transcriptomes in amygdala and PFC following fenofibrate, tesaglitazar and bezafibrate treatmentThe number of distinct and overlapping unique genes changed (p < 0.05) by treatment with fenofibrate (feno), tesaglitazar (tesa) and bezafibrate (beza) in the amygdala (A) and PFC (B). We assessed the gene-set containing feno- and tesa-responsive genes (excluding beza-responsive genes) for enriched pathways and gene ontologies because only feno and tesa decreased ethanol drinking. The boxes contain the overrepresented functional pathways and/or gene ontologies (hypergeometric p < 0.05). The number in parentheses beside the name of the pathway or ontology represents the number of genes in that category. Only selected pathways and ontologies are reported in this figure. Tables S7 – S9 provide the full list of the overrepresented KEGG/Wiki pathways and gene ontologies resulting from ORA of the key gene-sets for amygdala, PFC and liver.
Weighted gene co-expression network analysis of the transcriptome in the amygdala and PFC after PPAR agonist treatmentThe networks are displayed as a dendrogram where each leaf is a gene and the branches represent genes clustered together based on similar expression patterns across all samples. Branches were cut (i.e. modules were defined) using dynamic TreeCut function in R based on a cut height of 0.99. Similarity indicates interconnectedness, with genes closer to 1 being the most highly correlated. Modules are indicated by the arbitrary color bars. Treatment-responsiveness is indicated by the letter adjacent to the module under Drug (T, tesaglitazar; F, fenofibrate; B, bezafibrate). The modules that are responsive to both fenofibrate and tesaglitazar are outlined in red, and the direction of fold-change of the regulated genes is indicated by the arrow. Cell-type specific enrichment analysis results are indicated by the letter under Cell Type (N, neuron; O, oligodendrocyte; A, astrocyte; M, microglia; GLUT, glutamate; GABA, gamma-aminobutyric acid). A=amygdala; B=PFC.
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| Title | Year | PMID |
|---|---|---|
| Peroxisome proliferator-activated receptors α and γ are linked with alcohol consumption in mice and withdrawal and dependence in humans. | 2015 | 25516156 |
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