Project description:Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and cellular function in fibroblast from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARg) as a key contributor to CBD’s beneficial effects, and provide proof of dysregulated PPARg expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS.
Project description:Mutations in mitochondrial energy-producing genes lead to a heterogeneous group of untreatable disorders known as primary mitochondrial diseases (MD). Leigh syndrome (LS) is the most common pediatric MD and is characterized by progressive neuromuscular affectation and premature death. Here, we show that daily cannabidiol (CBD) administration significantly extends lifespan and ameliorates pathology in two LS mouse models, and improves cellular function in fibroblasts from LS patients. CBD delays motor decline and neurodegenerative signs, improves social deficits and breathing abnormalities, decreases thermally induced seizures, and improves neuropathology in affected brain regions. Mechanistically, we identify peroxisome proliferator-activated receptor gamma (PPARγ) as a key nuclear receptor mediating CBD's beneficial effects, while also providing proof of dysregulated PPARγ expression and activity as a common feature in both mouse neurons and fibroblasts from LS patients. Taken together, our results provide the first evidence for CBD as a potential treatment for LS.
Project description:While adipogenesis is controlled by a cascade of transcription factors, the global gene expression profiles in the early phase of adipogenesis are not well defined. Using microarray analysis of gene expression in 3T3-L1 cells we have identified evidence for the activity of 2568 genes during the early phase of adipocyte differentiation. One of these, ISL1, was of interest since its expression was markedly upregulated at 1 h after initiation of differentiation with a subsequent rapid decline. Overexpression of ISL1 at early times during adipocyte differentiation, but not at later times, was found to profoundly inhibit differentiation. This was accompanied by moderate down-regulation of PPARg levels, substantial down-regulation of PPARg downstream genes and down-regulation of BMP4 levels in preadipocytes. Readdition of BMP4 overcame the inhibitory effect of ISL1 on PPARg but not aP2 expression, a downstream gene of PPARg; and BMP4 also partially rescued ISL1 inhibition of adipogenesis, an effect which is additive with rosiglitazone. These results suggest that ISL1 is intimately involved in early regulation of adipogenesis, modulating PPARg expression and activity via BMP4-dependent and -independent mechanisms. Our time course gene expression survey sets the stage for further studies to explore other early and immediate regulators.
Project description:This SuperSeries is composed of the following subset Series: GSE16385: Expression data from human macrophages GSE16386: Expression data from human alternatively activated macrophages GSE25088: PPARg and IL-4-induced gene expression data from wild-type and STAT6 knockout mouse bone marrow-derived macrophages GSE25123: PPARg and IL-4-induced gene expression data from PPARg +/- LysCre and PPARg fl/- LysCre mouse bone marrow-derived macrophages GSE25125: PPARg and IL-4-induced gene expression data from PPARg +/- LysCre and PPARg fl/- LysCre mouse bone marrow-derived alternatively activated macrophages and immature dendritic cells (iDCs) Refer to individual Series
Project description:Clinically, obesity is strongly associated with severe TH2 immunopathology, though the physiological, cellular, and molecular underpinnings of this association remain obscure. We demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of TH2 immunopathology and disease burden in humans. Mechanistically, we show that dysregulation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARg) in T cells is a causal link between obesity and the increased TH2 immunopathology. We find that PPARg directly controls a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief TH2 effector cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13). Accordingly, thiazolidinediones (TZDs), potent PPARg agonists, robustly protect obese mice from TH2 immunopathology. Collectively, these findings establish PPARg as a molecular link between obesity and TH2 immune homeostasis and identify TZDs as novel therapeutic candidates for TH2 immunopathology.
Project description:We hypothesized that activation of PPARg would enhance myelination, reduce hydrocephalus, and promote neurological recovery in newborns with IVH. These hypotheses were tested in preterm rabbit model of IVH; autopsy brain samples from premature infants with and without IVH were analyzed. We found that IVH augmented PPARg expression in microglia of both preterm human infants and rabbit kits. The treatment with PPARg agonist or PPARg overexpression by adenovirus delivery further elevated PPARg levels in microglia, reduced pro-inflammatory cytokines, increased microglial phagocytosis, and improved oligodendrocyte progenitor cell (OPC) maturation in kits with IVH. Transcriptomic analyses of OPCs identified previously unrecognized PPARg-induced novel genes for purinergic signaling, cAMP generation, and antioxidant production, which would reprogram these progenitors toward promoting myelination. RNA-seq analyses of microglia revealed PPARg-triggered downregulation of several pro-inflammatory genes and transcripts having roles in Parkinson’s disease and amyotrophic lateral sclerosis, contributing to neurological recovery in kits with IVH. Accordingly, PPARg activation enhanced myelination and neurological function in kits with IVH.
Project description:Robust identification of placental PPARg target genes via mutliple PPARg-dependence criteria. Integration of differential expression data from Pparg-null, Rxra-null, Med1-nul and Ncoa6-null placentas and from WT and Pparg-null Trophoblast stem cells (TSC) differentiated for 2 or 4 days in the presence or absence of the PPARg agonist Rosiglitazone (Rosi).