PPAR agonists regulate brain gene expression: Relationship to their effects on ethanol consumption

Abstract

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.

Promising Pharmacogenetic Targets for Treating Alcohol Use Disorder: Evidence from Preclinical Models

“…PPARs are nuclear proteins that regulate gene expres sion and control neuroimmune responses and inflam mation [152]. Expression of PPARD (PPARδ subunit) and PPARGC1A (PPARγ coactivator) are altered in the basolateral and central amygdala of alcoholics [111], and PPAR agonists show promise in preclinical mod els of alcohol drinking, stressinduced relapse and withdrawal [153][154][155][156][157]. Because of the strong preclinical pharmacology and genetic data linking PPAR signal ing with alcohol intake, a clinical trial is currently underway to determine if the PPAR agonist fenofi brate will decrease craving for alcohol following cue exposure and reduce the number of drinks consumed in alcoholdependent subjects (ClinicalTrial.gov trial number: NCT02158273).…”

Neuroimmune Pathways in Alcohol Consumption: Evidence from Behavioral and Genetic Studies in Rodents and Humans

“…One study, however, showed that clofibrate increased voluntary alcohol consumption in male spontaneous hypertensive rats, although a very high ethanol concentration was used (30% ethanol, v/v) (Schlicht, 1987). The PPARα agonist, fenofibrate, and the dual PPARα/γ agonist, tesaglitazar, selectively decreased voluntary alcohol consumption and preference in mice (Blednov et al, submitted; Ferguson et al, 2014). Gene expression profiling revealed that fenofibrate and tesaglitazar changed the transcriptome of mouse amygdala and prefrontal cortex (Ferguson et al, 2014), two important brain areas for reward and dependence.…”

“…The PPARα agonist, fenofibrate, and the dual PPARα/γ agonist, tesaglitazar, selectively decreased voluntary alcohol consumption and preference in mice (Blednov et al, submitted; Ferguson et al, 2014). Gene expression profiling revealed that fenofibrate and tesaglitazar changed the transcriptome of mouse amygdala and prefrontal cortex (Ferguson et al, 2014), two important brain areas for reward and dependence. The list of PPAR agonist-regulated genes was dominated by known neuronal genes, which was unexpected given the importance of glial cells (especially microglia) in regulating neuroimmune and inflammatory signaling in brain (Ferguson et al, 2014).…”

“…Gene expression profiling revealed that fenofibrate and tesaglitazar changed the transcriptome of mouse amygdala and prefrontal cortex (Ferguson et al, 2014), two important brain areas for reward and dependence. The list of PPAR agonist-regulated genes was dominated by known neuronal genes, which was unexpected given the importance of glial cells (especially microglia) in regulating neuroimmune and inflammatory signaling in brain (Ferguson et al, 2014). Genes coding for proteins involved in synaptic plasticity and nerve impulse transmission were prominent.…”

“…Genes coding for proteins involved in synaptic plasticity and nerve impulse transmission were prominent. In the amygdala, genes involved in GABAergic, dopaminergic, and neuropeptide signaling were regulated in a coordinated manner (coexpressed) by the PPAR agonists, including many already known to alter alcohol consumption based on mutant mouse data (Ferguson et al, 2014). …”