β(2)-Adrenergic receptor (β(2)-AR) signaling activated by the agonist clenbuterol is important in the metabolism of muscle and adipose cells. Additionally, the significant role of histone demethylase JHDM2a in regulating metabolic gene expression was also recently demonstrated in Jhdm2a(-/-) mice. To elucidate the molecular mechanism involved in clenbuterol-induced adipocyte reduction from an epigenetic perspective, this study focused on cAMP-responsive element binding protein (CREB) to determine whether JHDM2a is regulated by the β(2)-AR/cAMP/protein kinase A (PKA) signaling pathway.
In porcine tissues treated with clenbuterol, JHDM2a expression was upregulated, and in porcine cells, expression of exogenous CREB led to increased JHDM2a expression. In addition, changes in JHDM2a expression were coincident with variations in the phosphorylation of CREB and p-CREB/CBP interaction in porcine and human cells treated with drugs known to modify the β(2)-AR/cAMP/PKA pathway. Finally, binding assays demonstrated that CREB regulated JHDM2a by binding directly to the CRE site nearest to the transcription start site.
Our results reveal that clenbuterol activates the β(2)-AR signaling pathway upstream of JHDM2a and that CREB acts as an intermediate link regulated by cAMP-PKA to induce activity of the JHDM2a promoter. These findings suggest that clenbuterol decreases adipose cell size and increases muscle fiber size in porcine tissues by virtue of JHDM2a-mediated demethylation, which regulates downstream metabolic and related genes.
[Show abstract][Hide abstract] ABSTRACT: AGR syndrome (the clinical triad of Aniridia, Genitourinary anomalies and mental Retardation, a subgroup of WAGR syndrome for Wilms tumor, Aniridia, Genitourinary anomalies and mental Retardation) is a rare syndrome caused by a contiguous gene deletion in the 11p13-14 region. However, the mechanisms of WAGR syndrome pathogenesis are elusive. In this study, we provide evidence that LGR4 (also named GPR48), the only G-protein coupled receptor (GPCR) gene in the human chromosome 11p12-11p14.4 fragment, is the key gene responsible for the diseases of AGR syndrome. Deletion of Lgr4 in mouse led to aniridia, polycystic kidney disease, genitourinary anomalies, and mental retardation, similar to the pathological defects of AGR syndrome. Furthermore, Lgr4 inactivation significantly increased cell apoptosis and decreased the expression of multiple important genes involved in the development of WAGR syndrome related organs. Specifically, deletion of Lgr4 down-regulated the expression of histone demethylases Jmjd2a and Fbxl10 through cAMP-CREB signaling pathways both in mouse embryonic fibroblast cells and in urinary and reproductive system mouse tissues. Our data suggest that Lgr4, which regulates eye, kidney, testis, ovary, and uterine organ development as well as mental development through genetic and epigenetic surveillance, is a novel candidate gene for the pathogenesis of AGR syndrome.
[Show abstract][Hide abstract] ABSTRACT: Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the β2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2(-/y)) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2(-/+)) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2(-/y) mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce β2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder.
Proceedings of the National Academy of Sciences 06/2014; 111(27). DOI:10.1073/pnas.1309426111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract DRG is of importance in relaying painful stimulation to the higher pain centers and therefore could be a crucial target for early intervention aimed at suppressing primary afferent stimulation. Complex regional pain syndrome (CRPS) is a common pain condition with an unknown etiology. Recently added new information enriches our understanding of CRPS pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, and mechanisms of pain modulation, central sensitization, and autonomic functions in CRPS revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of CRPS. Epigenetics refers to mitotically and meiotically heritable changes in gene expression that do not affect the DNA sequence. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, neurotransmitter responsiveness, and analgesic sensitivity, they are likely key factors in the development of chronic pain. In this dyad review series, we systematically examine the nerve injury-related changes in the neurological system and their contribution to CRPS. In this part, we first reviewed and summarized the role of neural sensitization in DRG neurons in performing function in the context of pain processing. Particular emphasis is placed on the cellular and molecular changes after nerve injury as well as different models of inflammatory and neuropathic pain. These were considered as the potential molecular bases that underlie nerve injury-associated pathogenesis of CRPS.
Medical science monitor: international medical journal of experimental and clinical research 06/2014; 20:1067-77. DOI:10.12659/MSM.890702 · 1.43 Impact Factor
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