scholarly journals Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Amy K. Rines ◽  
Hsiang-Chun Chang ◽  
Rongxue Wu ◽  
Tatsuya Sato ◽  
Arineh Khechaduri ◽  
...  
Keyword(s):  
Uncoupling Protein ◽  
Cardiac Cells ◽  
Dependent Manner ◽  
Mitochondrial Uncoupling ◽  
Metabolic Substrate ◽  
Ischaemia Reperfusion ◽  
Mitochondrial Efficiency ◽  
Substrate Usage ◽  
And Function ◽  
Amp Activated Protein Kinase

Abstract Ischaemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in tissue death. Here, we demonstrate that the AMP-activated protein kinase (AMPK)-related protein Snf1-related kinase (SNRK) decreases cardiac metabolic substrate usage and mitochondrial uncoupling, and protects against ischaemia/reperfusion. Hearts from transgenic mice overexpressing SNRK have decreased glucose and palmitate metabolism and oxygen consumption, but maintained power and function. They also exhibit decreased uncoupling protein 3 (UCP3) and mitochondrial uncoupling. Conversely, Snrk knockout mouse hearts have increased glucose and palmitate oxidation and UCP3. SNRK knockdown in cardiac cells decreases mitochondrial efficiency, which is abolished with UCP3 knockdown. We show that Tribbles homologue 3 (Trib3) binds to SNRK, and downregulates UCP3 through PPARα. Finally, SNRK is increased in cardiomyopathy patients, and SNRK reduces infarct size after ischaemia/reperfusion. SNRK also decreases cardiac cell death in a UCP3-dependent manner. Our results suggest that SNRK improves cardiac mitochondrial efficiency and ischaemic protection.

scholarly journals Corticosterone Enhances the AMPK-Mediated Immunosuppressive Phenotype of Testicular Macrophages During Uropathogenic Escherichia coli Induced Orchitis

2020 ◽  
Vol 11 ◽  
Author(s):  
Zhengguo Zhang ◽  
Ziming Jiang ◽  
Yiming Zhang ◽  
Yu Zhang ◽  
Yan Yan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Critical Event ◽  
M2 Macrophage ◽  
Mouse Bone Marrow ◽  
Dependent Manner ◽  
E Coli ◽  
And Function ◽  
Amp Activated Protein Kinase ◽  
Testicular Macrophages

Testicular macrophages (TM) play a central role in maintaining testicular immune privilege and protecting spermatogenesis. Recent studies showed that their immunosuppressive properties are maintained by corticosterone in the testicular interstitial fluid, but the underlying molecular mechanisms are unknown. In this study, we treated mouse bone marrow-derived macrophages (BMDM) with corticosterone (50 ng/ml) and uncovered AMP-activated protein kinase (AMPK) activation as a critical event in M2 polarization at the phenotypic, metabolic, and cytokine production level. Primary TM exhibited remarkably similar metabolic and phenotypic features to corticosterone-treated BMDM, which were partially reversed by AMPK-inhibition. In a murine model of uropathogenic E. coli-elicited orchitis, intraperitoneal injection with corticosterone (0.1mg/day) increased the percentage of M2 TM in vivo, in a partially AMPK-dependent manner. This study integrates the influence of corticosterone on M2 macrophage metabolic pathways, phenotype, and function, and highlights a promising new avenue for the development of innovative therapeutics for orchitis patients.

Hydroxynonenal-stimulated activity of the uncoupling protein in Acanthamoeba castellanii mitochondria under phosphorylating conditions

2013 ◽  
Vol 394 (5) ◽  
pp. 649-658 ◽  
Author(s):  
Andrzej Woyda-Ploszczyca ◽  
Wieslawa Jarmuszkiewicz
Keyword(s):  
Respiratory Rate ◽  
Atp Synthase ◽  
Redox State ◽  
Uncoupling Protein ◽  
Acanthamoeba Castellanii ◽  
Complex Iii ◽  
Dependent Manner ◽  
Mitochondrial Uncoupling ◽  
Concentration Dependent Manner ◽  
Succinate Oxidation

Abstract The influence of 4-hydroxy-2-nonenal (HNE), a lipid peroxidation end product, on the activity of the amoeba Acanthamoeba castellanii uncoupling protein (AcUCP) in isolated phosphorylating mitochondria was studied. Under phosphorylating conditions, exogenously added HNE induced GTP-sensitive AcUCP-mediated mitochondrial uncoupling. The HNE-induced proton leak decreased the yield of oxidative phosphorylation in an HNE concentration-dependent manner. The present study describes how the contributions of ATP synthase and HNE-induced AcUCP in phosphorylating respiration vary when the rate of succinate oxidation is decreased by limiting succinate uptake or inhibiting complex III activity within the range of a constant membrane potential. In phosphorylating mitochondria, at a given HNE concentration (100 μm), the efficiency of AcUCP in mitochondrial uncoupling increased as the respiratory rate decreased because the AcUCP contribution remained constant while the ATP synthase contribution decreased with the respiratory rate. HNE-induced uncoupling can be inhibited by GTP only when ubiquinone is sufficiently oxidized, indicating that in phosphorylating A. castellanii mitochondria, the sensitivity of AcUCP activity to GTP depends on the redox state of the membranous ubiquinone.

scholarly journals Adipose tissue growth and development: the modulating role of ambient temperature

2021 ◽  
Vol 248 (1) ◽  
pp. R19-R28
Author(s):  
Michael E Symonds ◽  
Mark Pope ◽  
Ian Bloor ◽  
James Law ◽  
Reham Alagal ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Ambient Temperature ◽  
Uncoupling Protein ◽  
Tissue Growth ◽  
Long Term Effects ◽  
Mitochondrial Uncoupling ◽  
Fat Depots ◽  
Brown Adipose ◽  
Beige Fat ◽  
And Function

Adipose tissue is usually laid down in small amounts in the foetus and is characterised as possessing small amounts of the brown adipose tissue-specific mitochondrial uncoupling protein (UCP)1. In adults, a primary factor determining the abundance and function of UCP1 is ambient temperature. Cold exposure causes activation and the rapid generation of heat through the free flow of protons across the mitochondria with no requirement to convert ADP to ATP. In rodents, housing at an ambient temperature below thermoneutrality promotes the appearance of beige like adipocytes. These arise as discrete regions of UCP1 containing cells in white fat depots. There is increasing evidence to show that to gain credible translational results on brown and beige fat function in rodent models that they should be housed at thermoneutrality. This not only reflects the type of environment in which humans spend a majority of their time, but is in accord with the rise of global temperature caused by industrialisation and the uncontrolled burning of fossil fuels. There is now good evidence in adult humans, that stimulating brown fat can improve glucose homeostasis which can be achieved either by nutritional or pharmacological interventions. The challenge, therefore, is to establish credible developmental models in animals maintained at thermoneutrality which will elucidate the true impact of nutrition. The primary focus should fall specifically on the components of breast milk and how these modulate long term effects on brown or beige fat development and function.

scholarly journals Melatonin Regulates Differentiation of Sheep Brown Adipocyte Precursor Cells Via AMP-Activated Protein Kinase

2021 ◽  
Vol 8 ◽  
Author(s):  
Xu-Yang Gao ◽  
Bu-Hao Deng ◽  
Xin-Rui Li ◽  
Yu Wang ◽  
Jian-Xin Zhang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Precursor Cells ◽  
Brown Adipocyte ◽  
Nuclear Antigen ◽  
Economic Losses ◽  
Dependent Manner ◽  
Brown Adipose ◽  
And Function ◽  
Amp Activated Protein Kinase ◽  
Adipocyte Precursor

In sheep industry, hypothermia caused by insufficient brown adipose tissue (BAT) deposits is one of the major causes of lamb deaths. Enhancing the formation and function of BAT in neonatal lamb increases thermogenesis and hence reduces economic losses. The aim of the present study was to explore the effect and mechanism of melatonin on sheep brown adipocyte formation and function. Sheep brown adipocyte precursor cells (SBACs) isolated from perirenal BAT were treated with melatonin (1 and 10 nM). The SBACs subjected to melatonin exhibited a decreased proliferation ability, accompanied by down-regulated proliferating cell nuclear antigen, cyclin D1, and CDK4 protein contents in a melatonin dose-dependent manner. Melatonin promoted brown adipocyte formation and induced the expression of brown adipogenic markers, including uncoupling protein 1 and PR domain-containing 16 during differentiation of SBAC. Moreover, the AMP-activated protein kinase α1 (AMPKα1) activity was positively correlated with brown adipocyte formation potential. Importantly, melatonin effectively activated AMPKα1. Furthermore, promotional effects of melatonin were abolished by AMPKα1 knockout, suggesting the involvement of AMPKα1 in this process. Collectively, these results suggested that melatonin enhanced brown adipocyte formation in SBACs in vitro through activation of AMPKα1.

scholarly journals Polyphenols from Blue Honeysuckle (Lonicera caerulea L. var. edulis) Berry Inhibit Lipid Accumulation in Adipocytes by Suppressing Lipogenesis

2021 ◽  
Author(s):  
Xinxin Liu ◽  
Ying Lv ◽  
Mengyu Zheng ◽  
Li Yin ◽  
Xiqing Wang ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Fatty Acid Synthase ◽  
Uncoupling Protein ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Composition Analysis ◽  
Dependent Manner ◽  
Intracellular Lipid Accumulation ◽  
Amp Activated Protein Kinase ◽  
Blue Honeysuckle

Polyphenols have been shown to possess outstanding anti-obesity properties. In this study, the effect of blue honeysuckle berry extract (BHBE) with high polyphenol content on lipid accumulation in adipocytes and the underlying mechanism were investigated for the first time. Composition analysis demonstrated that flavonoids (mainly flavonols and anthocyanins) were the primary polyphenols in BHBE, which contributed to its biological functions. The results of Oil Red O staining combined with triglyceride (TG) content determination showed that BHBE exhibited an obvious inhibitory effect on intracellular lipid accumulation in a dose-dependent manner. BHBE also reduced the protein level of fatty acid synthase (FAS) and increased the phosphorylation level of acetyl-CoA carboxylase (ACC), indicating that lipogenesis was suppressed by BHBE treatment. Moreover, BHBE was found to significantly promote the phosphorylation of AMP-activated protein kinase (AMPK) and further reduce the expression of key transcription factors (PPARγ, C/EBPα, and SREBP-1c) that regulate lipogenesis. In addition, the expression of beige adipocyte markers (Tmem26 and Cd137) and uncoupling protein 1 (UCP1) was increased in BHBE-treated adipocytes. In summary, we consider that BHBE inhibits lipid accumulation in adipocytes by suppressing lipogenesis as well as by promoting beiging of adipocytes. These results support blue honeysuckle berry as a candidate functional food against obesity.

Abstract 14048: Snf1-related Kinase Improves Cardiac Metabolic Efficiency through a Decrease in Mitochondrial Uncoupling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Amy K Rines ◽  
Rongxue Wu ◽  
Arineh Khechaduri ◽  
Michael A Burke ◽  
Tatsuya Sato ◽  
...  
Keyword(s):  
Uncoupling Protein ◽  
Sequence Similarity ◽  
Ischemia Reperfusion ◽  
Gene Array ◽  
Cardiac Cells ◽  
Acid Oxidation ◽  
Metabolic Efficiency ◽  
Area At Risk ◽  
Wild Type Littermate ◽  
Mitochondrial Uncoupling

Introduction: Snf1-related Kinase (SNRK) is a serine/threonine kinase with sequence similarity to AMP-activated protein kinase, but its function is unknown. We found that SNRK is increased in hearts from patients with ischemic cardiomyopathy, and our gene array data suggested that SNRK alters metabolic genes. Here, we assessed the hypothesis that SNRK regulates cardiac metabolic efficiency. Results: Transgenic (TG) mice with cardiac-specific overexpression of SNRK were generated, and displayed decreased glycolysis (1267.66 vs. 1925.60 nmol/min/g, n=6), glucose oxidation (441.73 vs. 602.68 nmol/min/g), and palmitate oxidation (262.39 vs. 385.07 nmol/min/g) compared to wild type littermate controls in perfused working hearts. However, cardiac power, contractility, ATP, and triglyceride and glycogen stores were maintained, while oxygen consumption was reduced, suggesting that SNRK TG mice have increased metabolic efficiency. The hearts also exhibited decreased uncoupling protein 3 (UCP3) expression, mitochondrial uncoupling, and peroxisome proliferator-activated receptor α (PPARα) expression. SNRK homozygous knockout (KO) was embryonic lethal, but hearts from heterozygous SNRK KO mice had increased glucose and fatty acid oxidation and increased expression of UCP3 and PPARα. SNRK knockdown in cardiac cells also increased UCP3, mitochondrial depolarization, and substrate flux, which were all reversed with UCP3 knockdown. The SNRK-mediated changes in UCP3 were PPARα-dependent. To determine the mechanism of PPARα and UCP3 regulation by SNRK, we performed a yeast two hybrid screen and identified Tribbles homolog 3 (Trib3) as a binding partner of SNRK. SNRK transgenic mice had increased Trib3 expression, and Trib3 overexpression reversed the upregulation of PPARα and UCP3 by SNRK knockdown. Finally, SNRK overexpression in mice reduced infarct size compared to area-at-risk (53.01% vs. 37.95%, n=6) in response to myocardial ischemia/reperfusion. Conclusions: Our results demonstrate that SNRK increases cardiac metabolic efficiency and protects against ischemic damage through binding and upregulation of Trib3, leading to PPARα-driven UCP3 downregulation and improved mitochondrial coupling.

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