A history of UCPI

2001 ◽  
Vol 29 (6) ◽  
pp. 751-755 ◽  
Author(s):  
D. G. Nicholls
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Uncoupling Protein ◽  
Respiratory Control ◽  
Receptor Activation ◽  
Protonmotive Force ◽  
Acid Activation ◽  
Outer Face ◽  
Purine Nucleotides ◽  
Brown Adipose

Interest in the enormous thermogenic capacity of brown adipose tissue (BAT) began in the 1960s and focused on BAT mitochondria (BATM), which when prepared by conventional techniques respired rapidly but displayed no respiratory control. Two apparently distinct treatments, fatty acid removal and purine nucleotide addition, induced respiratory control. In 1972, we found that BATM were highly permeant to halides and protons, and that albumin decreased the proton conductance while purine nucleotides decreased both. Devising techniques to quantify the proton leak in respiring mitochondria we found a nucleotide-sensitive conductance pathway whose ‘break-point’, the protonmotive force at which conductance suddenly increased, could be subtly modulated by free fatty acids. The nucleotide-binding site on the outer face of the inner membrane was characterized and identified by photoaffinity labelling as a 32 kDa ‘uncoupling protein’, now UCP1. Studies with intact brown adipocytes generated the currently accepted model, namely that fatty acids liberated by β3-adrenergic receptor activation act as both self-regulating second messengers for UCP1 and substrates for fatty acid activation and oxidation. Fatty acid concentration increases at the outset of thermogenesis, binding to UCP1 lowers the protonmotive force below that giving respiratory control and rapid thermogenesis proceeds. At the termination of receptor activation oxidation of residual fatty acid ‘recouples’ the mitochondria. The challenge with the novel UCPs is to demonstrate a similar coherent mechanism.

scholarly journals A comparative study of the inhibitory effects of purine nucleotides and carboxyatractylate on the uncoupling protein-3 and adenine nucleotide translocase.

2010 ◽  
Vol 57 (4) ◽  
Author(s):  
Natalia P Komelina ◽  
Zarif G Amerkhanov
Keyword(s):  
Fatty Acid ◽  
Adenine Nucleotide ◽  
Uncoupling Protein ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
Ground Squirrels ◽  
Adenine Nucleotide Translocase ◽  
Purine Nucleotides ◽  
Chloride Permeability ◽  
Brown Adipose

Uncoupling proteins (UCPs) mediate fatty acid-induced proton cycling in mitochondria, which is stimulated by superoxide and inhibited by GDP. Fatty acid anions can also be transported by adenine nucleotide translocase (ANT), thus resulting in the uncoupling of oxidative phosphorylation. In the present work, an attempt was made to distinguish between the protonophoric activity of UCP3 and that of ANT using inhibition analysis. This study was carried out using mitochondria from skeletal muscles of hibernating Yakut ground squirrel, which have a significant level of UCP3 mRNA. We found that millimolar concentrations of GDP, which is considered to be a specific inhibitor of UCPs, slightly recoupled the mitochondrial respiration and restored the membrane potential. Addition of the specific ANT inhibitor CAT (carboxyatractylate), in micromolar concentration, prior to GDP prevented its recoupling effect. Moreover, GDP and ADP exhibited a competitive kinetic behavior with respect to ANT. In brown adipose tissue, CAT did not prevent the UCP1-iduced increase in chloride permeability and the inhibitory effect of GDP, thus confirming the inability of CAT to affect UCP1. These results allow us to conclude that the recoupling effect of purine nucleotides on skeletal muscle mitochondria of hibernating ground squirrels can be explained by interaction of the nucleotides with ANT, whereas UCP3 is not involved in the process.

The energetic implications of uncoupling protein-3 in skeletal muscle

2007 ◽  
Vol 32 (5) ◽  
pp. 884-894 ◽  
Author(s):  
Sheila R. Costford ◽  
Erin L. Seifert ◽  
Véronic Bézaire ◽  
Martin F. Gerrits ◽  
Lisa Bevilacqua ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Proton Leak ◽  
Ros Production ◽  
Uncoupling Protein 3 ◽  
Brown Adipose ◽  
Mitochondrial Fatty Acid

Despite almost a decade of research since the identification of uncoupling protein-3 (UCP3), the molecular mechanisms and physiological functions of this mitochondrial anion carrier protein are not well understood. Because of its highly selective expression in skeletal muscle and the existence of mitochondrial proton leak in this tissue, early reports proposed that UCP3 caused a basal proton leak and increased thermogenesis. However, gene expression data and results from knockout and overexpression studies indicated that UCP3 does not cause basal proton leak or physiological thermogenesis. UCP3 expression is associated with increases in circulating fatty acids and in fatty acid oxidation (FAO) in muscle. Fatty acids are also well recognized as activators of the prototypic UCP1 in brown adipose tissue. This has led to hypotheses implicating UCP3 in mitochondrial fatty acid translocation. The corresponding hypothesized physiological roles include facilitated FAO and protection from the lipotoxic effects of fatty acids. Recent in vitro studies of physiological increases in UCP3 in muscle cells demonstrate increased FAO, and decreased reactive oxygen species (ROS) production. Detailed mechanistic studies indicate that ROS or lipid by-products of ROS can activate a UCP3-mediated proton leak, which in turn acts in a negative feedback loop to mitigate ROS production. Altogether, UCP3 appears to play roles in muscle FAO and mitigated ROS production. Future studies will need to elucidate the molecular mechanisms underlying increased FAO, as well as the physiological relevance of ROS-activated proton leak.

Uncoupling protein 1 inhibition by purine nucleotides is under the control of the endogenous ubiquinone redox state

2009 ◽  
Vol 424 (2) ◽  
pp. 297-306 ◽  
Author(s):  
Aleksandra Swida-Barteczka ◽  
Andrzej Woyda-Ploszczyca ◽  
Francis E. Sluse ◽  
Wieslawa Jarmuszkiewicz
Keyword(s):  
Fatty Acid ◽  
Redox State ◽  
Uncoupling Protein ◽  
Yeast Mitochondria ◽  
Purine Nucleotide ◽  
Uncoupling Protein 1 ◽  
Purine Nucleotides ◽  
State Dependent ◽  
Brown Adipose ◽  
The Relationship

We studied non-esterified fatty acid-induced uncoupling of heterologously expressed rat UCP1 (uncoupling protein 1) in yeast mitochondria, as well as UCP1 in rat BAT (brown adipose tissue) mitochondria. The proton-conductance curves and the relationship between the ubiquinone reduction level and membrane potential were determined in non-phosphorylating BAT and yeast mitochondria. The ADP/O method was applied to determine the ADP phosphorylation rate and the relationship between the ubiquinone reduction level and respiration rate in yeast mitochondria. Our studies of the membranous ubiquinone reduction level in mitochondria demonstrate that activation of UCP1 leads to a purine nucleotide-sensitive decrease in the ubiquinone redox state. Results obtained for non-phosphorylating and phosphorylating mitochondria, as the endogenous ubiquinone redox state was gradually varied by a lowering rate of the ubiquinone-reducing or ubiquinol-oxidizing pathways, indicate that the endogenous ubiquinone redox state has no effect on non-esterified fatty acid-induced UCP1 activity in the absence of GTP, and can only regulate this activity through sensitivity to inhibition by the purine nucleotide. At a given oleic acid concentration, inhibition by GTP diminishes when ubiquinone is reduced sufficiently. The ubiquinone redox state-dependent alleviation of UCP1 inhibition by the purine nucleotide was observed at a high ubiquinone reduction level, when it exceeded 85–88%.

Acute Central Infusion of Leptin Modulates Fatty Acid Mobilization by Affecting Lipolysis and mRNA Expression for Uncoupling Proteins

2005 ◽  
Vol 230 (3) ◽  
pp. 200-206 ◽  
Author(s):  
Daisuke Tajima ◽  
Takayuki Masaki ◽  
Shuji Hidaka ◽  
Tetsuya Kakuma ◽  
Toshiie Sakata ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Lipolytic Activity ◽  
Uncoupling Protein ◽  
Hormone Sensitive Lipase ◽  
Saline Control ◽  
Energy Substrates ◽  
Fatty Acid Binding ◽  
Brown Adipose

Chronic administration of leptin has been shown to reduce adiposity through energy intake and expenditure. The present study alms to examine how acute central infusion of leptin regulates peripheral lipid metabolism, as assessed by markers indicative of their mobilization and utilization. A bolus infusion of 1 μg/rat leptin into the third cerebroventricle increased the expression of mRNA for hormone-sensitive lipase (HSL), an indicator of lipolysis, in white adipose tissue (WAT). This was accompanied by elevation of plasma levels of glycerol, but not of free fatty acids, as compared to the saline control (P < 0.03). The same treatment with leptin decreased plasma insulin levels but did not affect the plasma glucose level (P < 0.05 for insulin). Among the major regulators of the transportation or utilization of energy substrates, leptin treatment increased expression of mRNA for uncoupling protein 1 (UCP1) in brown adipose tissue (BAT), UCP2 in WAT, and UCP3 in quadriceps skeletal muscle, but not those for fatty acid–binding protein in WAT, carnitine phosphate transferase-1, a marker for β oxidation of fatty acids in muscle, nor glucose transporter 4 in WAT and muscle (P < 0.01 for HSL, P < 0.05 for UCP1, and P < 0.005 for UCP2 and UCP3). These results indicate that, even in a single bolus, leptin may regulate the mobilization and/or utilization of energy substrates such as fatty acids by affecting lipolytic activity in WAT and by increasing the expression of UCPs in BAT, WAT, and muscle.

scholarly journals Redirection of lipid flux toward phospholipids in yeast increases fatty acid turnover and secretion

2018 ◽  
Vol 115 (6) ◽  
pp. 1262-1267 ◽  
Author(s):  
Raphael Ferreira ◽  
Paulo Gonçalves Teixeira ◽  
Verena Siewers ◽  
Jens Nielsen
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Metabolic Network ◽  
Feedback Regulation ◽  
Acid Activation ◽  
Phospholipid Hydrolysis ◽  
Microbial Cell Factories ◽  
Cell Factories ◽  
High Level

Bio-based production of fatty acids and fatty acid-derived products can enable sustainable substitution of petroleum-derived fuels and chemicals. However, developing new microbial cell factories for producing high levels of fatty acids requires extensive engineering of lipid metabolism, a complex and tightly regulated metabolic network. Here we generated a Saccharomyces cerevisiae platform strain with a simplified lipid metabolism network with high-level production of free fatty acids (FFAs) due to redirected fatty acid metabolism and reduced feedback regulation. Deletion of the main fatty acid activation genes (the first step in β-oxidation), main storage lipid formation genes, and phosphatidate phosphatase genes resulted in a constrained lipid metabolic network in which fatty acid flux was directed to a large extent toward phospholipids. This resulted in simultaneous increases of phospholipids by up to 2.8-fold and of FFAs by up to 40-fold compared with wild-type levels. Further deletion of phospholipase genes PLB1 and PLB2 resulted in a 46% decrease in FFA levels and 105% increase in phospholipid levels, suggesting that phospholipid hydrolysis plays an important role in FFA production when phospholipid levels are increased. The multiple deletion mutant generated allowed for a study of fatty acid dynamics in lipid metabolism and represents a platform strain with interesting properties that provide insight into the future development of lipid-related cell factories.

scholarly journals Enhanced Fatty Acid Flux Triggered by Adiponectin Overexpression

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 113-122 ◽  
Author(s):  
Shoba Shetty ◽  
Maria A. Ramos-Roman ◽  
You-Ree Cho ◽  
Jonathan Brown ◽  
Jorge Plutzky ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Uncoupling Protein ◽  
Retinol Binding Protein ◽  
Peroxisome Proliferator ◽  
Tissue Mass ◽  
Triglyceride Synthesis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Brown Adipose

Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in free fatty acid turnover in plasma (15.1 ± 1.5 vs. 25.3 ± 6.8 mg/kg · min, P = 0.011). ADNTg mice had 2-fold more brown adipose tissue mass, and triglyceride synthesis and turnover were 5-fold greater in this organ (P = 0.046). Epididymal white adipose tissue was slightly reduced, possibly due to the approximately 1.5-fold increase in the expression of genes involved in oxidation (peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1α, and uncoupling protein 3). In ADNTg liver, lipogenic gene expression was reduced, but there was an unexpected increase in the expression of retinoid pathway genes (hepatic retinol binding protein 1 and retinoic acid receptor beta and adipose Cyp26A1) and liver retinyl ester content (64% higher, P &lt; 0.02). Combined, these data support a physiological link between adiponectin signaling and increased efficiency of triglyceride synthesis and hydrolysis, a process that can be controlled by retinoids. Interactions between adiponectin and retinoids may underlie adiponectin's effects on intermediary metabolism.

scholarly journals Steroid Hormones Control Circadian Elovl3 Expression in Mouse Liver

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 3158-3166 ◽  
Author(s):  
Annelie Brolinson ◽  
Stéphane Fourcade ◽  
Andreas Jakobsson ◽  
Aurora Pujol ◽  
Anders Jacobsson
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Steroid Hormones ◽  
Mouse Liver ◽  
Atp Binding ◽  
Mrna Levels ◽  
Male Mice ◽  
Brown Adipose ◽  
Long Chain ◽  
Atp Binding Cassette

The Elovl3 gene belongs to the Elovl gene family, which encodes for enzymes involved in the elongation of very long chain fatty acids. The recognized role for the enzyme is to control the elongation of saturated and monounsaturated fatty acids up to 24 carbons in length. Elovl3 was originally identified as a highly expressed gene in brown adipose tissue on cold exposure. Here we show that hepatic Elovl3 mRNA expression follows a distinct diurnal rhythm exclusively in mature male mice, with a sharp increase early in the morning Zeitgeber time (ZT) 20, peaks around ZT2, and is back to basal level at the end of the light period at ZT10. In female mice and sexually immature male mice, the Elovl3 expression was constantly low. Fasting and refeeding mice with chow or high-fat diet did not alter the Elovl3 mRNA levels. However, animals that were exclusively fed during the day for 9 d displayed an inverted expression profile. In addition, we show that Elovl3 expression is transcriptionally controlled and significantly induced by the exposure of the synthetic glucocorticoid dexamethasone. Taken together, these data suggest that Elovl3 expression in mouse liver is under strict diurnal control by circulating steroid hormones such as glucocorticoids and androgens. Finally, Elovl3 expression was found to be elevated in peroxisomal transporter ATP-binding cassette, subfamily D(ALD), member 2 ablated mice and suppressed in ATP-binding cassette subfamily D(ALD) member 2 overexpressing mice, implying a tight cross talk between very long chain fatty acid synthesis and peroxisomal fatty acid oxidation.

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