scholarly journals BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes

2020 ◽  
Vol 3 (9) ◽  
pp. e201900619
Author(s):  
Hyoung Kyu Kim ◽  
Tae Hee Ko ◽  
In-Sung Song ◽  
Yu Jeong Jeong ◽  
Hye Jin Heo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Therapeutic Potential ◽  
Cardiac Contractility ◽  
Camp Response Element Binding ◽  
Mitochondrial Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Calcium Calmodulin Dependent ◽  
Element Binding Protein ◽  
Underlying Mechanisms

Diabetic cardiomyopathy (DCM) is a major cause of mortality/morbidity in diabetes mellitus patients. Although tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous cardiovascular target, its effect on myocardial cells and mitochondria in DCM and the underlying mechanisms remain unknown. Here, we determined the involvement of BH4 deficiency in DCM and the therapeutic potential of BH4 supplementation in a rodent DCM model. We observed a decreased BH4:total biopterin ratio in heart and mitochondria accompanied by cardiac remodeling, lower cardiac contractility, and mitochondrial dysfunction. Prolonged BH4 supplementation improved cardiac function, corrected morphological abnormalities in cardiac muscle, and increased mitochondrial activity. Proteomics analysis revealed oxidative phosphorylation (OXPHOS) as the BH4-targeted biological pathway in diabetic hearts as well as BH4-mediated rescue of down-regulated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) signaling as a key modulator of OXPHOS and mitochondrial biogenesis. Mechanistically, BH4 bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and activated downstream AMP-activated protein kinase/cAMP response element binding protein/PGC-1α signaling to rescue mitochondrial and cardiac dysfunction in DCM. These results suggest BH4 as a novel endogenous activator of CaMKK2.

scholarly journals Effects of Caloric Intake on Learning and Memory Function in Juvenile C57BL/6J Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Bao-Lei Xu ◽  
Rong Wang ◽  
Li-Na Ma ◽  
Wen Dong ◽  
Zhi-Wei Zhao ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Memory Function ◽  
Caloric Intake ◽  
Camp Response Element Binding ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Downstream Effectors ◽  
Element Binding Protein

Dietary composition may influence neuronal function as well as processes underlying synaptic plasticity. In this study, we aimed to determine the effect of high and low caloric diets on a mouse model of learning and memory and to explore mechanisms underlying this process. Mice were divided into three different dietary groups: normal control(n=12), high-caloric (HC) diet(n=12), and low-caloric (LC) diet(n=12). After 6 months, mice were evaluated on the Morris water maze to assess spatial memory ability. We found that HC diet impaired learning and memory function relative to both control and LC diet. The levels of SIRT1 as well as its downstream effectors p53, p16, and peroxisome proliferator-activated receptorγ(PPARγ) were decreased in brain tissues obtained from HC mice. LC upregulated SIRT1 but downregulated p53, p16, and PPARγ. The expressions of PI3K and Akt were not altered after HC or LC diet treatment, but both LC and HC elevated the levels of phosphorylated-cAMP response element-binding protein (p-CREB) and IGF-1 in hippocampal CA1 region. Therefore, HC diet-induced dysfunction in learning and memory may be prevented by caloric restriction via regulation of the SIRT1-p53 or IGF-1 signaling pathways and phosphorylation of CREB.

scholarly journals Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory

2018 ◽  
Vol 115 (31) ◽  
pp. E7408-E7417 ◽  
Author(s):  
Dhruv Patel ◽  
Avik Roy ◽  
Madhuchhanda Kundu ◽  
Malabendu Jana ◽  
Chi-Hao Luan ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Calcium Influx ◽  
Hippocampal Slices ◽  
Direct Interaction ◽  
Camp Response Element Binding ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hippocampal Plasticity ◽  
Element Binding Protein

Despite its long history, until now, no receptor has been identified for aspirin, one of the most widely used medicines worldwide. Here we report that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor involved in fatty acid metabolism, serves as a receptor of aspirin. Detailed proteomic analyses including cheminformatics, thermal shift assays, and TR-FRET revealed that aspirin, but not other structural homologs, acts as a PPARα ligand through direct binding at the Tyr314 residue of the PPARα ligand-binding domain. On binding to PPARα, aspirin stimulated hippocampal plasticity via transcriptional activation of cAMP response element-binding protein (CREB). Finally, hippocampus-dependent behavioral analyses, calcium influx assays in hippocampal slices and quantification of dendritic spines demonstrated that low-dose aspirin treatment improved hippocampal plasticity and memory in FAD5X mice, but not in FAD5X/Ppara-null mice. These findings highlight a property of aspirin: stimulating hippocampal plasticity via direct interaction with PPARα.

Epinephrine and AICAR-induced PGC-1α mRNA expression is intact in skeletal muscle from rats fed a high-fat diet

2012 ◽  
Vol 302 (12) ◽  
pp. C1772-C1779 ◽  
Author(s):  
Bruce C. Frier ◽  
Zhongxiao Wan ◽  
Deon B. Williams ◽  
Amanda L. Stefanson ◽  
David C. Wright
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
High Fat Diet ◽  
Camp Response Element Binding ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Male Wistar Rats ◽  
Amp Activated Protein Kinase

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis and is controlled, at least in part, through AMP-activated protein kinase and p38-dependent pathways. There is evidence demonstrating that activation of these kinases and induction of PGC-1α in skeletal muscle are regulated by catecholamines. The purpose of the present study was to determine if consumption of a high-fat diet (HFD) impairs epinephrine and 5-aminoimidazole-4-carboxamide-1β-d-ribofuranoside (AICAR) signaling and induction of PGC-1α in rat skeletal muscle. Male Wistar rats were fed chow or a HFD for 6 wk and then given a weight-adjusted bolus injection of epinephrine (20, 10, or 5 μg/100 g body wt sc) or saline, and triceps muscles were harvested 30 min (signaling) or 2 and 4 h (gene expression) postinjection. Despite blunted increases in p38 phosphorylation, the ability of epinephrine to induce PGC-1α was intact in skeletal muscle from HFD-fed rats and was associated with normal increases in activation of PKA and phosphorylation of cAMP response element-binding protein, reputed mediators of PGC-1α expression. The attenuated epinephrine-mediated increase in p38 phosphorylation was independent of increases in MAPK phosphatase 1. At 2 h following AICAR treatment (0.5 g/kg body wt sc), AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation were similar in skeletal muscle from chow- and HFD-fed rats. Surprisingly, AICAR-induced increases in PGC-1α mRNA levels were greater in skeletal muscle from HFD-fed rats. Our results demonstrate that the ability of epinephrine and AICAR to induce PGC-1α remains intact in skeletal muscle from HFD-fed rats. These results question the existence of reduced β-adrenergic responsiveness in diet-induced obesity and demonstrate that increases in p38 phosphorylation are not required for induction of PGC-1α in muscle from obese rats.

scholarly journals Estradiol Acts Directly and Indirectly on Multiple Signaling Pathways to Phosphorylate cAMP-Response Element Binding Protein in GnRH Neurons

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3792-3803 ◽  
Author(s):  
Rachel Y. Cheong ◽  
Andrea Kwakowsky ◽  
Zsuzsanna Barad ◽  
Robert Porteous ◽  
Allan E. Herbison ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Camp Response Element Binding ◽  
Type Ii ◽  
Camp Response Element ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Gnrh Neurons ◽  
Element Binding Protein ◽  
Dependent Protein

Rapid, nonclassical 17β-estradiol (E2) actions are thought to play an important role in the modulation of neuronal function. The present study addresses the intracellular signaling cascades involved in the rapid E2-induced phosphorylation of cAMP response element binding protein (CREB) in GnRH neurons. Administration of E2 to adult female mice resulted in the activation of ERK1/2 in GnRH neurons within 15 min. In vitro studies using pharmacological antagonists showed that ERK1/2 was essential for E2-induced CREB phosphorylation in GnRH neurons. Upstream to this, protein kinase A and calcium/calmodulin-dependent protein kinase type II, but not protein kinase C, were found to be necessary for E2-induced phosphorylation of ERK1/2. This rapid E2 signaling cascade in GnRH neurons was found to require both direct and indirect E2 actions. E2 failed to phosphorylate ERK1/2 and CREB in GnRH neuron-specific estrogen receptor β knockout mice in vivo. Equally, however, a cocktail of tetrodotoxin and γ-aminobutyric acidA/glutamate receptor antagonists also blocked E2-induced ERK1/2 phosphorylation in GnRH neurons in wild-type mice in vitro. Together, these observations indicate that E2 acts through calcium/calmodulin-dependent protein kinase type II and protein kinase A to rapidly phosphorylate ERK1/2, which then acts to phosphorylate CREB in adult female GnRH neurons. Intriguingly, these effects of E2 are dependent upon both direct ERβ mechanisms as well as indirect actions mediated by afferent inputs to GnRH neurons.

Role of PPARγ in renoprotection in Type 2 diabetes: molecular mechanisms and therapeutic potential

2008 ◽  
Vol 116 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Jichun Yang ◽  
Dongjuan Zhang ◽  
Jing Li ◽  
Xiaoyan Zhang ◽  
Fenling Fan ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Large Body ◽  
Underlying Mechanism ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Underlying Mechanisms ◽  
Stage Renal Disease

DN (diabetic nephropathy) is a chronic disease characterized by proteinuria, glomerular hypertrophy, decreased glomerular filtration and renal fibrosis with loss of renal function. DN is the leading cause of ESRD (end-stage renal disease), accounting for millions of deaths worldwide. TZDs (thiazolidinediones) are synthetic ligands of PPARγ (peroxisome-proliferator-activated receptor γ), which is involved in many important physiological processes, including adipose differentiation, lipid and glucose metabolism, energy homoeostasis, cell proliferation, inflammation, reproduction and renoprotection. A large body of research over the past decade has revealed that, in addition to their insulin-sensitizing effects, TZDs play an important role in delaying and preventing the progression of chronic kidney disease in Type 2 diabetes. Although PPARγ activation by TZDs is in general considered beneficial for the amelioration of diabetic renal complications in Type 2 diabetes, the underlying mechanism(s) remains only partially characterized. In this review, we summarize and discuss recent findings regarding the renoprotective effects of PPARγ in Type 2 diabetes and the potential underlying mechanisms.

scholarly journals Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

2015 ◽  
Vol 112 (48) ◽  
pp. E6683-E6690 ◽  
Author(s):  
Atish Mukherji ◽  
Ahmad Kobiita ◽  
Pierre Chambon
Keyword(s):  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Active Phase ◽  
Camp Response Element Binding ◽  
Circadian Clocks ◽  
Metabolic Reprogramming ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Alterations ◽  
Element Binding Protein

The molecular mechanisms underlying the events through which alterations in diurnal activities impinge on peripheral circadian clocks (PCCs), and reciprocally how the PCCs affect metabolism, thereby generating pathologies, are still poorly understood. Here, we deciphered how switching the diurnal feeding from the active to the rest phase, i.e., restricted feeding (RF), immediately creates a hypoinsulinemia during the active phase, which initiates a metabolic reprogramming by increasing FFA and glucagon levels. In turn, peroxisome proliferator-activated receptor alpha (PPARα) activation by free fatty acid (FFA), and cAMP response element-binding protein (CREB) activation by glucagon, lead to further metabolic alterations during the circadian active phase, as well as to aberrant activation of expression of the PCC components nuclear receptor subfamily 1, group D, member 1 (Nr1d1/RevErbα), Period (Per1 and Per2). Moreover, hypoinsulinemia leads to an increase in glycogen synthase kinase 3β (GSK3β) activity that, through phosphorylation, stabilizes and increases the level of the RevErbα protein during the active phase. This increase then leads to an untimely repression of expression of the genes containing a RORE DNA binding sequence (DBS), including the Bmal1 gene, thereby initiating in RF mice a 12-h PCC shift to which the CREB-mediated activation of Per1, Per2 by glucagon modestly contributes. We also show that the reported corticosterone extraproduction during the RF active phase reflects an adrenal aberrant activation of CREB signaling, which selectively delays the activation of the PPARα–RevErbα axis in muscle and heart and accounts for the retarded shift of their PCCs.

Ca2+/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression

2007 ◽  
Vol 32 (5) ◽  
pp. 921-929 ◽  
Author(s):  
Robin N. Michel ◽  
Eva R. Chin ◽  
Joe V. Chakkalakal ◽  
Joe K. Eibl ◽  
Bernard J. Jasmin
Keyword(s):  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Peroxisome Proliferator ◽  
Force Output ◽  
Activated T Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hypertrophic Growth

Ca2+ signalling plays an important role in excitation–contraction coupling and the resultant force output of skeletal muscle. It is also known to play a crucial role in modulating both short- and long-term muscle cellular phenotypic adaptations associated with these events. Ca2+ signalling via the Ca2+/calmodulin (CaM)-dependent phosphatase calcineurin (CnA) and via Ca2+/CaM-dependent kinases, such as CaMKI and CaMKII, is known to regulate hypertrophic growth in response to overload, to direct slow versus fast fibre gene expression, and to contribute to mitochondrial biogenesis. The CnA- and CaMK-dependent regulation of the downstream transcription factors nuclear factor of activated T cells (NFAT) and myocyte-specific enhancer factor 2 are known to activate muscle-specific genes associated with a slower, more oxidative fibre phenotype. We have also recently shown the expression of utrophin A, a cytoskeletal protein that accumulates at the neuromuscular junction and plays a role in maturation of the postsynaptic apparatus, to be regulated by CnA–NFAT and Ca2+/CaM signalling. This regulation is fibre-type specific and potentiated by interactions with the transcriptional regulators and coactivators GA binding protein (also known as nuclear respiratory factor 2) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Another downstream target of CnA signalling may be myostatin, a transforming growth factor-β family member that is a negative regulator of muscle growth. While the list of the downstream targets of CnA/NFAT- and Ca2+/CaM-dependent signalling is emerging, the precise interaction of these pathways with the Ca2+-independent pathways p38 mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2, phosphoinositide-3 kinase, and protein kinase B (Akt/PKB) must also be considered when deciphering fibre responses and plasticity to altered contractile load.

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