Peroxisome Proliferator-Activated Receptor β/δ in the Brain: Facts and Hypothesis

peroxisome proliferator-activated receptors (PPARs) are nuclear receptors acting as lipid sensors. Besides its metabolic activity in peripheral organs, the PPAR beta/delta isotype is highly expressed in the brain and its deletion in mice induces a brain developmental defect. Nevertheless, exploration of PPARβ action in the central nervous system remains sketchy. The lipid content alteration observed in PPARβ null brains and the positive action of PPARβ agonists on oligodendrocyte differentiation, a process characterized by lipid accumulation, suggest that PPARβ acts on the fatty acids and/or cholesterol metabolisms in the brain. PPARβ could also regulate central inflammation and antioxidant mechanisms in the damaged brain. Even if not fully understood, the neuroprotective effect of PPARβ agonists highlights their potential benefit to treat various acute or chronic neurological disorders. In this perspective, we need to better understand the basic function of PPARβ in the brain. This review proposes different leads for future researches

A point mutation in the AF-2 domain of thyroid hormone receptor alpha1 expressed after CRE mediated recombination partially recapitulates hypothyroidism.

Thyroid hormones act directly on transcription by binding to TRα1, TRβ1, TRβ2 nuclear receptors, regulating many aspects of post-natal development and homeostasis. To precisely analyze the implication of the widely expressed TRα1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TRα1 coding sequence, which is expressed only after CRE/loxP mediated DNA recombination. The amino-acid change prevents interaction between TRα1 and histone acetyltransferase coactivators and the release of corepressors. Early expression of this dominant-negative receptor deeply affects post-natal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TRβ1 and TRβ2 are predominantly expressed. Both respective abundance and intrinsic properties of TRα1 and TRβ1/2 seems to govern specificity of action

Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice.

Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargF <sup>Δ/Δ</sup> ) and whole-body PPARγ-null (Pparg <sup>Δ/Δ</sup> ) mice. We identified a clear sex dimorphism occurring only in Pparg <sup>Δ/Δ</sup> mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized Pparg <sup>Δ/Δ</sup> mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex-biased genes were particularly perturbed in both sexes, affecting lipid metabolism, drug metabolism, inflammatory and cellular stress response pathways. Most importantly, we found that the expression of key sex-biased genes was severely affected in all the NAFLD models we tested. Thus, hepatosteatosis strongly affects hepatic sex-biased gene expression. With NAFLD increasing in prevalence, this emphasizes the urgent need to specifically address the consequences of this deregulation in humans

Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)alpha 1 and TR alpha 2: clinical, biochemical, and genetic analyses of three related patients

Background The thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TRα1 and TRα2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TRα1, to delineate the relative roles of TRα1 and TRα2. Methods We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence. Findings The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine:free tri-iodothyronine [T3], low concentration of total reverse T3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TRα1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TRα1 and TRα2 proteins. The Ala263Val mutant TRα1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TRα2 matched its normal counterpart. In vitro, high concentrations of T3 restored transcriptional activity of Ala263Val mutant TRα1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells. Interpretation TRα1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA. Funding Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Marie Curie Actions, Foundation for Development of Internal Medicine in Europe

Maternal thyroid hormones are essential for neural development in Zebrafish

Teleost eggs contain an abundant store of maternal thyroid hormones (THs), and early in zebrafish embryonic development, all the genes necessary for TH signaling are expressed. Nonetheless the function of THs in embryonic development remains elusive. To test the hypothesis that THs are fundamental for zebrafish embryonic development, an monocarboxilic transporter 8 (Mct8) knockdown strategy was deployed to prevent maternal TH uptake. Absence of maternal THs did not affect early specification of the neural epithelia but profoundly modified later dorsal specification of the brain and spinal cord as well as specific neuron differentiation. Maternal THs acted upstream of pax2a, pax7, and pax8 genes but downstream of shha and fgf8a signaling. The lack of inhibitory spinal cord interneurons and increased motoneurons in the mct8 morphants is consistent with their stiff axial body and impaired mobility. The mct8 mutations are associated with X-linked mental retardation in humans, and the cellular and molecular consequences of MCT8 knockdown during embryonic development in zebrafish provides new insight into the potential role of THs in this condition.Portuguese Science Foundation (FCT) [PTDC/MAR/115005/2009]; FCT [SFRH/BPD/66808/2009, SFRH/BPD/67008/2009, Pest-OE/EQB/LA0023/2013]info:eu-repo/semantics/publishedVersio

Genome-Wide Search Reveals the Existence of a Limited Number of Thyroid Hormone Receptor Alpha Target Genes in Cerebellar Neurons

Thyroid hormone (T3) has a major influence on cerebellum post-natal development. The major phenotypic landmark of exposure to low levels of T3 during development (hypothyroidism) in the cerebellum is the retarded inward migration of the most numerous cell type, granular neurons. In order to identify the direct genetic regulation exerted by T3 on cerebellar neurons and their precursors, we used microarray RNA hybridization to perform a time course analysis of T3 induced gene expression in primary cultures of cerebellar neuronal cell. These experiments suggest that we identified a small set of genes which are directly regulated, both in vivo and in vitro, during cerebellum post-natal development. These modest changes suggest that T3 does not acts directly on granular neurons and mainly indirectly influences the cellular interactions taking place during development

Follicle-Stimulating Hormone Receptor: Advances and Remaining Challenges

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EFFETS PHYSIOLOGIQUES ET PATHOGENIQUES DE L'APORECEPTEUR DE L'HORMONE THYROÏDIENNE ALPHA 1 AU COURS DU DEVELOPPEMENT DE LA SOURIS

Date de rédaction : Février / Mars 2007Thyroid hormone (T3) has pleiotropic functions during development. Congenital hypothyroidism results in severe mental retardation. Using transgenic reporter mice, we showed that T3 action is highly heterogeneous in pre and post-natal brain. The regulation of gene expression by T3 involves binding of the hormone to TR nuclear receptors acting as T3-dependant transcription factors. We identified new T3 direct target genes in postnatal cerebellum, but the T3 signaling cascade is still unknown, because of complexe cell cell interactions. To suppress T3 response in a specific cell type and at a specific time, we created new transgenic mice expressing a mutated TR?1 in a conditional manner. Constitutive mutants have a hypothyroid like phenotype. This confirms the importance of unliganded TR?1 receptor in hypothyroidism pathogenesis. The conditional system will permit to dissect in vivo T3 action.L'hormone thyroïdienne (T3) a des fonctions pléiotropiques au cours du développement. Un déficit congénital de T3 est responsable d'un retard mental sévère. Grâce à des souris possédant un transgène rapporteur, nous avons montré que l'activité de l'hormone est très hétérogène dans le cerveau pré et post-natal. T3 agit via les récepteurs nucléaires TR pour réguler la transcription de gènes-cibles. De nouveaux gènes-cibles ont été identifiés dans le cervelet post-natal, mais la cascade de signalisation demeure inconnue, en raison d'interactions cellulaires complexes. Pour supprimer la réponse à T3 à un moment donné, dans une cellule donnée, des souris exprimant de façon conditionnelle un récepteur TR?1 muté ont été générées. Les mutants constitutifs ont un phénotype très proche de l'hypothyroïdie, ce qui confirme l'implication majeure du récepteur TR?1 non lié à T3 dans la pathogénie de l'hypothyroïdie. Le système conditionnel permettra de disséquer le mécanisme d'action de T3 in vivo