scholarly journals Carboxyatractyloside effects on brown-fat mitochondria imply that the adenine nucleotide translocator isoforms ANT1 and ANT2 may be responsible for basal and fatty-acid-induced uncoupling respectively

2006 ◽  
Vol 399 (3) ◽  
pp. 405-414 ◽  
Author(s):  
Irina G. Shabalina ◽  
Tatiana V. Kramarova ◽  
Jan Nedergaard ◽  
Barbara Cannon
Keyword(s):  
Fatty Acid ◽  
Adenine Nucleotide ◽  
Liver Mitochondria ◽  
Basal Respiration ◽  
Brown Fat ◽  
Proton Leak ◽  
Mrna Levels ◽  
Adenine Nucleotide Translocator ◽  
Brown Adipose ◽  
Brown Fat Mitochondria

In brown-fat mitochondria, fatty acids induce thermogenic uncoupling through activation of UCP1 (uncoupling protein 1). However, even in brown-fat mitochondria from UCP1−/− mice, fatty-acid-induced uncoupling exists. In the present investigation, we used the inhibitor CAtr (carboxyatractyloside) to examine the involvement of the ANT (adenine nucleotide translocator) in the mediation of this UCP1-independent fatty-acid-induced uncoupling in brown-fat mitochondria. We found that the contribution of ANT to fatty-acid-induced uncoupling in UCP1−/− brown-fat mitochondria was minimal (whereas it was responsible for nearly half the fatty-acid-induced uncoupling in liver mitochondria). As compared with liver mitochondria, brown-fat mitochondria exhibit a relatively high (UCP1-independent) basal respiration (‘proton leak’). Unexpectedly, a large fraction of this high basal respiration was sensitive to CAtr, whereas in liver mitochondria, basal respiration was CAtr-insensitive. Total ANT protein levels were similar in brown-fat mitochondria from wild-type mice and in liver mitochondria, but the level was increased in brown-fat mitochondria from UCP1−/− mice. However, in liver, only Ant2 mRNA was found, whereas in brown adipose tissue, Ant1 and Ant2 mRNA levels were equal. The data are therefore compatible with a tentative model in which the ANT2 isoform mediates fatty-acid-induced uncoupling, whereas the ANT1 isoform may mediate a significant part of the high basal proton leak in brown-fat mitochondria.

scholarly journals Thyroid-hormone control of state-3 respiration in isolated rat liver mitochondria

1990 ◽  
Vol 265 (3) ◽  
pp. 731-734 ◽  
Author(s):  
R P Hafner ◽  
G C Brown ◽  
M D Brand
Keyword(s):  
Thyroid Hormone ◽  
Atp Synthase ◽  
Adenine Nucleotide ◽  
Liver Mitochondria ◽  
Proton Leak ◽  
Rat Liver Mitochondria ◽  
Protonmotive Force ◽  
Adenine Nucleotide Translocator ◽  
Hormone Control ◽  
Kinetics Of

Oxidative phosphorylation can be treated as two groups of reactions; those that generate protonmotive force (dicarboxylate carrier, succinate dehydrogenase and the respiratory chain) and those that consume protonmotive force (adenine nucleotide and phosphate carriers. ATP synthase and proton leak). Mitochondria from hypothyroid rats have lower rates of respiration in the presence of ADP (state 3) than euthyroid controls. We show that the kinetics of the protonmotive-force generators are unchanged in mitochondria from hypothyroid animals, but the kinetics of the protonmotive-force consumers are altered, supporting proposals that the important effects of thyroid hormone on state 3 are on the ATP synthase or the adenine nucleotide translocator.

GDP binding to rat brown fat mitochondria: effects of thyroxine at different ambient temperatures

1981 ◽  
Vol 241 (3) ◽  
pp. C134-C139 ◽  
Author(s):  
U. Sundin
Keyword(s):  
Linear Increase ◽  
Reciprocal Relationship ◽  
Brown Fat ◽  
Hormone Activity ◽  
Ambient Temperatures ◽  
Heating Capacity ◽  
Brown Adipose ◽  
Induced Changes ◽  
Brown Fat Mitochondria

Reports on a reciprocal relationship between sympathetic-nerve and experimentally induced changes in thyroid-hormone activity called into question the proposed role of thyroxine in the changes seen in the brown fat after cold adaptation. Rats reared at +30, +22, and +5 degrees C received daily injections of thyroxine (1 mg/kg). After 3 wk of treatment, the thermogenic state of the tissue was assessed by measuring the capacity of the brown fat mitochondria to bind guanosine 5'-diphosphate (GDP). GDP-inhibited mitochondrial swelling, brown adipose tissue (BAT) wet weights, and mitochondrial yields were also measured. The control animals showed a linear increase in GDP binding between +30 and +5 degrees C. Thyroxine was found to lower the GDP binding markedly at +5 degrees C, less so at +22 degrees C, while no effect was evident at +30 degrees C. The values at +22 and +30 degrees C were identical. The other parameters studied all confirmed these results. The conclusion made is that the thyroxine-induced rise in basal metabolic rate lowers the critical temperature and reduces the demand for nonshivering thermogenesis. This is reflected in the reduced GDP binding and hence heating capacity of the brown fat mitochondria.

Effect of noradrenaline chronic administration on brown fat phospholipids

1988 ◽  
Vol 8 (5) ◽  
pp. 465-469 ◽  
Author(s):  
Gérard Mory ◽  
Myriam Gawer ◽  
Jean-Claude Kader
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Brown Adipose Tissue ◽  
Acid Composition ◽  
Cold Exposure ◽  
Chronic Administration ◽  
Sympathetic Tone ◽  
Brown Fat ◽  
Brown Adipose

Chronic cold exposure of rats (9 days at 5°C) induces an alteration of the fatty acid composition of phospholipids in brown adipose tissue. The alteration is due to an increase of the unsaturation degree of these lipids. The phenomenon can be reproduced by 10−7 mole. h−1 administration of noradrenaline for 9 days in rats kept at 25°C. Thus, phospholipid alteration in brown fat of cold exposed rats is most probably a consequence of the increase of sympathetic tone which occurs in this tissue during exposure to cold.

Influence of subdiaphragmatic vagotomy and brown fat sympathectomy on thermogenesis in rats

1985 ◽  
Vol 249 (3) ◽  
pp. E239-E243 ◽  
Author(s):  
P. L. Andrews ◽  
N. J. Rothwell ◽  
M. J. Stock
Keyword(s):  
Insulin Treatment ◽  
Brown Fat ◽  
Guanosine Diphosphate ◽  
Subdiaphragmatic Vagotomy ◽  
Brown Adipose ◽  
Adrenergic Antagonist ◽  
Brown Adipose Tissue Activity ◽  
Acute Injection ◽  
Brown Fat Mitochondria ◽  
Thermogenic Response

Infusion of rats with insulin (8 U/day via implanted minipump) for 7 days caused a 22% rise in resting oxygen consumption, which was inhibited by acute injection of the beta-adrenergic antagonist propranolol. Insulin treatment produced significant increases in brown fat mass, protein content, and total thermogenic activity (assessed from binding of guanosine diphosphate to isolated brown fat mitochondria), but these responses were inhibited by prior surgical sympathectomy of the tissue. Animals subjected to subdiaphragmatic vagotomy gained more weight than pair-fed, sham-operated controls and showed reductions in total energy expenditure, the acute thermogenic response to a meal and brown adipose tissue activity. Daily injections of insulin (1 U/day) prevented all of these effects of vagotomy. These data demonstrate that the changes in brown fat activity induced by exogenous insulin are mediated by the sympathetic nervous system and that the depressed thermogenesis and brown fat activity associated with vagotomy appear to be due to a relative insulin deficiency and can be reversed by treatment with the hormone.

scholarly journals Aromatase Deficiency Inhibits the Permeability Transition in Mouse Liver Mitochondria

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1643-1652 ◽  
Author(s):  
Loredana Moro ◽  
Arnaldo A. Arbini ◽  
Jer-Tsong Hsieh ◽  
Jeffery Ford ◽  
Evan R. Simpson ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Mitochondrial Permeability Transition ◽  
Adenine Nucleotide ◽  
Mitochondrial Protein ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Estrogen Deficiency ◽  
Mrna Levels ◽  
Mitochondrial Membranes ◽  
Mitochondrial Permeability

Lack of estrogens affects male physiology in a number of ways, including severe changes in liver metabolism that result in lipid accumulation and massive hepatic steatosis. Here we investigated whether estrogen deficiency may alter the functionality and permeability properties of liver mitochondria using, as an experimental model, aromatase knockout (ArKO) male mice, which cannot synthesize endogenous estrogens due to a disruption of the Cyp19 gene. Liver mitochondria isolated from ArKO mice displayed increased activity of the mitochondrial respiratory complex IV compared with wild-type mice and were less prone to undergo cyclosporin A-sensitive mitochondrial permeability transition (MPT) induced by calcium loading. The altered permeability properties of the mitochondrial membranes were not due to changes in reactive oxygen species, ATP levels, or mitochondrial membrane potential but were associated with increased content of the phospholipid cardiolipin, structural component of the mitochondrial membranes and regulator of the MPT pore, and with increased mitochondrial protein levels of Bcl-2 and the adenine nucleotide translocator (ANT), regulator and component of the MPT pore, respectively. Real-time RT-PCR demonstrated increased mRNA levels for Bcl-2 and ANT2 but not for the ANT1 isoform in ArKO livers. Supplementation of 17β-estradiol retrieved ArKO mice from massive hepatic steatosis and restored mitochondrial permeability properties, cardiolipin, Bcl-2, and ANT2 levels. Overall, our findings demonstrate an important role of estrogens in the modulation of hepatic mitochondrial function and permeability properties in males and suggest that estrogen deficiency may represent a novel positive regulator of Bcl-2 and ANT2 proteins, two inhibitors of MPT occurrence and powerful antiapoptotic molecules.

scholarly journals Mechanism of Fatty-Acid-Dependent UCP1 Uncoupling in Brown Fat Mitochondria

Cell ◽  
2012 ◽  
Vol 151 (2) ◽  
pp. 400-413 ◽  
Author(s):  
Andriy Fedorenko ◽  
Polina V. Lishko ◽  
Yuriy Kirichok
Keyword(s):  
Fatty Acid ◽  
Brown Fat ◽  
Brown Fat Mitochondria

Reduced adiposity and improved insulin sensitivity in obese mice with antisense suppression of 4E-BP2 expression

2008 ◽  
Vol 294 (3) ◽  
pp. E530-E539 ◽  
Author(s):  
Xing Xian Yu ◽  
Sanjay K. Pandey ◽  
Sheri L. Booten ◽  
Susan F. Murray ◽  
Brett P. Monia ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Homeostasis ◽  
Fatty Acid Synthase ◽  
Initiation Factor ◽  
Synthesis Rate ◽  
Mrna Levels ◽  
Obese Mice ◽  
Brown Adipose ◽  
Hepatic Glucose ◽  
Glucose Output

To investigate the possible role of eukaryotic initiation factor 4E-binding protein-2 (4E-BP2) in metabolism and energy homeostasis, high-fat diet-induced obese mice were treated with a 4E-BP2-specific antisense oligonucleotide (ASO) or a control 4E-BP2 ASO at a dose of 25 mg/kg body wt or with saline twice a week for 6 wk. 4E-BP2 ASO treatment reduced 4E-BP2 levels by >75% in liver and white (WAT) and brown adipose (BAT) tissues. Treatment did not change food intake but lowered body weight by ∼7% and body fat content by ∼18%. Treatment decreased liver triglyceride (TG) content by >50%, normalized plasma glucose and insulin levels, and reduced glucose excursion during glucose tolerance test. 4E-BP2 ASO-treated mice showed >8.5% increase in metabolic rate, >40% increase in UCP1 levels in BAT, >45% increase in β3-adrenoceptor mRNA, and 40–55% decrease in mitochondrial dicarboxylate carrier, fatty acid synthase, and diacylglycerol acyltransferase 2 mRNA levels in WAT. 4E-BP2 ASO-transfected mouse hepatocytes showed an increased fatty acid oxidation rate and a decreased TG synthesis rate. In addition, 4E-BP2 ASO-treated mice demonstrated ∼60 and 29% decreases in hepatic glucose-6-phosphatase and phospho enolpyruvate carboxykinase mRNA, respectively, implying decreased hepatic glucose output. Furthermore, increased phosphorylation of AktSer473 in both liver and fat of 4E-BP2 ASO-treated mice and increased GLUT4 levels in plasma membrane in WAT of the ASO-treated mice were observed, indicating enhanced insulin signaling and increased glucose uptake as a consequence of reduced 4E-BP2 expression. These data demonstrate for the first time that peripheral 4E-BP2 plays an important role in metabolism and energy homeostasis.

Differential regulation of fatty acid elongation enzymes in brown adipocytes implies a unique role for Elovl3 during increased fatty acid oxidation

2005 ◽  
Vol 289 (4) ◽  
pp. E517-E526 ◽  
Author(s):  
Andreas Jakobsson ◽  
Johanna A. Jörgensen ◽  
Anders Jacobsson
Keyword(s):  
Fatty Acid ◽  
Gene Family ◽  
Regulatory Element ◽  
Saturated Fatty Acids ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Cold Stimulation ◽  
Brown Adipocytes ◽  
Brown Adipose

The expression of the Elovl3 gene, which belongs to the Elovl gene family coding for microsomal enzymes involved in very long-chain fatty acid (VLCFA) elongation, is dramatically increased in mouse brown adipose tissue upon cold stimulation. In the present study, we show that the cold-induced Elovl3 expression is under the control of peroxisome proliferator-activated receptor-α (PPARα) and that this regulation is part of a fundamental divergence in the regulation of expression for the different members of the Elovl gene family. In cultured brown adipocytes, a mixture of norepinephrine, dexamethasone, and the PPARα ligand Wy-14643, which rendered the adipocytes a high oxidative state, was required for substantial induction of Elovl3 expression, whereas the same treatment suppressed Elovl1 mRNA levels. The nuclear liver X receptor (LXR) has been implicated in the control of fatty acid synthesis and subsequent lipogenic processes in several tissues. This regulation is also exerted in part by sterol regulatory element-binding protein (SREBP-1), which is a target gene of LXR. We found that stimulation of Elovl3 expression was independent of LXR and SREBP-1 activation. In addition, exposure to the LXR agonist TO-901317 increased nuclear abundance of LXR and mature SREBP-1 as well as expression of the elongases Lce and Elovl1 in a lipogenic fashion but repressed Elovl3 expression. A functional consequence of this was seen on the level of esterified saturated fatty acids, such as C22:0, which was coupled to Elovl3 expression. These data demonstrate differential transcriptional regulation and concomitantly different functional roles for fatty acid elongases in lipid metabolism of brown adipocytes, which reflects the metabolic status of the cells.

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