scholarly journals Endurance training increases stimulation of uncoupling of skeletal muscle mitochondria in humans by non-esterified fatty acids: an uncoupling-protein-mediated effect?

2000 ◽  
Vol 351 (3) ◽  
pp. 805-810 ◽  
Author(s):  
Michail TONKONOGI ◽  
Anna KROOK ◽  
Brandon WALSH ◽  
Kent SAHLIN
Keyword(s):  
Fatty Acids ◽  
Endurance Training ◽  
Uncoupling Protein ◽  
Mrna Level ◽  
Relative Increase ◽  
Essential Property ◽  
Mrna Levels ◽  
Purine Nucleotides ◽  
Muscle Mitochondria ◽  
Esterified Fatty Acids

Uncoupled respiration (UCR) is an essential property of muscle mitochondria and has several functions in the cell. We hypothesized that endurance training may alter the magnitude and properties of UCR in human muscle. Isolated mitochondria from muscle biopsies taken before and after 6 weeks of endurance exercise training (n = 8) were analysed for UCR. To investigate the role of uncoupling protein 2 (UCP2) and UCP3 in UCR, the sensitivity of UCR to UCP-regulating ligands (non-esterified fatty acids and purine nucleotides) and UCP2 and UCP3 mRNA expression in muscle were examined. Oleate increased the mitochondrial oxygen consumption rate, an effect that was not attenuated by GDP and/or cyclosporin A. The effect of oleate was significantly greater after compared with before training. Training had no effect on UCP2 or UCP3 mRNA levels, but after training the relative increase in respiration rate induced by oleate was positively correlated with the UCP2 mRNA level. In conclusion, we show that the sensitivity of UCR to non-esterified fatty acids is up-regulated by endurance training. This suggests that endurance training causes intrinsic changes in mitochondrial function, which may enhance the potential for regulation of aerobic energy production, prevent excess free radical generation and contribute to a higher basal metabolic rate.

Whole body metabolic effects of prolonged endurance training in combination with erythropoietin treatment in humans: a randomized placebo controlled trial

2013 ◽  
Vol 305 (7) ◽  
pp. E879-E889 ◽  
Author(s):  
Britt Christensen ◽  
Birgitte Nellemann ◽  
Mads S. Larsen ◽  
Line Thams ◽  
Peter Sieljacks ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Endurance Training ◽  
Exercise Capacity ◽  
Uncoupling Protein ◽  
Metabolic Effects ◽  
Whole Body ◽  
Mrna Levels ◽  
Healthy Humans ◽  
Ucp2 Mrna

Erythropoietin (Epo) administration improves aerobic exercise capacity and insulin sensitivity in renal patients and also increases resting energy expenditure (REE). Similar effects are observed in response to endurance training. The aim was to compare the effects of endurance training with erythropoiesis-stimulating agent (ESA) treatment in healthy humans. Thirty-six healthy untrained men were randomized to 10 wk of either: 1) placebo ( n = 9), 2) ESA ( n = 9), 3) endurance training ( n = 10), or 4) ESA and endurance training ( n = 8). In a single-blinded design, ESA/placebo was injected one time weekly. Training consisted of biking for 1 h at 65% of wattmax three times per week. Measurements performed before and after the intervention were as follows: body composition, maximal oxygen uptake, insulin sensitivity, REE, and palmitate turnover. Uncoupling protein 2 (UCP2) mRNA levels were assessed in skeletal muscle. Fat mass decreased after training ( P = 0.003), whereas ESA induced a small but significant increase in intrahepatic fat ( P = 0.025). Serum free fatty acid (FFA) levels and palmitate turnover decreased significantly in response to training, whereas the opposite pattern was found after ESA. REE corrected for lean body mass increased in response to ESA and training, and muscle UCP2 mRNA levels increased after ESA ( P = 0.035). Insulin sensitivity increased only after training ( P = 0.011). In conclusion: 1) insulin sensitivity is not improved after ESA treatment despite improved exercise capacity, 2) the calorigenic effects of ESA may be related to increased UCP2 gene expression in skeletal muscle, and 3) training and ESA exert opposite effects on lipolysis under basal conditions, increased FFA levels and liver fat fraction was observed after ESA treatment.

scholarly journals Control of Hep G2-cell triacylglycerol and apolipoprotein B synthesis and secretion by polyunsaturated non-esterified fatty acids and insulin

1992 ◽  
Vol 288 (1) ◽  
pp. 101-107 ◽  
Author(s):  
C D Byrne ◽  
T W M Wang ◽  
C N Hales
Keyword(s):  
Fatty Acids ◽  
Apolipoprotein B ◽  
Cellular Protein ◽  
Mrna Levels ◽  
Hep G2 ◽  
Apo B ◽  
Esterified Fatty Acids ◽  
Affect Cell Viability ◽  
Intracellular Content ◽  
Cellular Protein Content

Non-esterified fatty acids (NEFAs) and insulin are important factors in the control of lipoprotein secretion, but the mechanism of action is unclear. The present study was undertaken to determine whether insulin and NEFAs modulated hepatic secretion of triacylglycerol and apolipoprotein B (apo-B) by regulation of hepatic intracellular apo-B content. The experiments were performed with the human hepatoblastoma cell line Hep G2, for periods of up to 72 h in the presence and absence of NEFAs and insulin. Higher concentrations of eicosapentanoate (EPA) sustained for 72 h decreased cellular protein content (at 250 microM) or caused cell death (at 750 microM), and this effect was not observed with the other NEFAs studied, whereas 75 microM-EPA did not affect cell viability. Compared with the absence of NEFA, 75 microM-EPA did not alter the intracellular triacylglycerol content, but decreased the intracellular content of apo-B by 47% (P < 0.01) and decreased secreted triacylglycerol and secreted apo-B by 13% (P < 0.05) and 21% (P < 0.01) respectively, after 72 h. However 250 microM-oleate increased the intracellular triacylglycerol by 36% (P < 0.01), intracellular apo-B by 22% (P < 0.05) and secreted triacylglycerol and apo-B by 20-30% (P < 0.05-0.01). Insulin decreased secreted triacylglycerol and apo-B in the presence of each NEFA studied by 20-30%. There was no correlation between the changes in intracellular triacylglycerol and the rate of secretion. However, when the secreted triacylglycerol or apo-B was plotted against intracellular apo-B content a significant correlation was observed (r = 0.89, P < 0.001 for both analyses). Apo-B mRNA levels did not change after 72 h incubation with oleate or EPA. These results demonstrate that EPA can be toxic to hepatocytes and that NEFAs and insulin control secretion of triacylglycerol and apo-B by regulation of the intracellular apo-B concentration, thus controlling assembly of apo-B with triacylglycerol to form lipoproteins.

In vivo regulation of SREBP-1c in skeletal muscle: effects of nutritional status, glucose, insulin, and leptin

2004 ◽  
Vol 287 (1) ◽  
pp. R218-R227 ◽  
Author(s):  
S. Renee Commerford ◽  
Li Peng ◽  
John J. Dubé ◽  
Robert M. O'Doherty
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Nutritional Status ◽  
Fatty Acid Synthase ◽  
Gastrocnemius Muscle ◽  
Uncoupling Protein ◽  
Regulatory Element ◽  
Mrna Level ◽  
Mrna Levels ◽  
Fas Mrna

Sterol regulatory element binding protein-1c (SREBP-1c), a transcription factor that is important for mediating insulin effects on metabolic gene expression in liver during the fasted-to-fed transition, is also expressed in skeletal muscle. However, the regulation and role of SREBP-1c in skeletal muscle are poorly understood. The present study compared the effects of nutritional status, physiological hyperinsulinemic clamps, and adenovirus-mediated hyperleptinemia (HLEP) in rats on expression of SREBP-1c and other metabolic genes in skeletal muscle. Three- and 6-h refeeding of 18-h-fasted animals increased levels of SREBP-1c mRNA and the SREBP-1 protein (full length and mature) in gastrocnemius muscle ( P < 0.05). Fatty acid synthase (FAS) and hexokinase II (HKII) mRNA levels were also increased by refeeding, and uncoupling protein 3 (UCP3) mRNA level was decreased (all P < 0.05). Surprisingly, 3-h hyperinsulinemic clamps did not increase gastrocnemius muscle SREBP-1c and FAS mRNA levels or SREBP-1 protein levels but did increase HKII mRNA levels and decrease UCP3 mRNA levels ( P < 0.05). HLEP reduced refeeding-induced increases of SREBP-1c and FAS mRNA levels but did not reduce the level of SREBP-1 protein. We conclude that 1) skeletal muscle SREBP-1c gene expression is regulated by nutritional status in a fashion similar to that observed in liver and adipose tissue, 2) physiological hyperinsulinemia is not sufficient to imitate the effects of refeeding on SREBP-1c gene expression, and 3) leptin suppresses refeeding effects on SREBP-1c mRNA levels.

Increased plasma non-esterified fatty acids and platelet-activating factor acetylhydrolase are associated with susceptibility to atherosclerosis in mice

2004 ◽  
Vol 106 (4) ◽  
pp. 421-432 ◽  
Author(s):  
Uma SINGH ◽  
Shumei ZHONG ◽  
Momiao XIONG ◽  
Tong-bin LI ◽  
Allan SNIDERMAN ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Animal Models ◽  
Enzyme Activities ◽  
Platelet Activating Factor ◽  
Density Lipoprotein ◽  
Mrna Levels ◽  
Wild Type ◽  
Platelet Activating Factor Acetylhydrolase ◽  
Esterified Fatty Acids

Animal models provide vital tools to explicate the pathogenesis of atherosclerosis. Accordingly, we established two atherosclerosis-prone mice models: (i) mice lacking the LDL (low-density lipoprotein) receptor (LDLR) and the ability to edit apo (apolipoprotein) B mRNA (Apobec1; designated LDb: LDLR-/-Apobec1-/-), and (ii) mice with the LDb background, who also overexpressed human apoB100 (designated LTp: LDLR-/-Apobec1-/-ERhB+/+). Both LDb and LTp mice had markedly elevated levels of LDL and increased levels of NEFAs (non-esterified fatty acids) compared with C57BL/6 wild-type mice. However, fasting glucose and insulin levels in both animals were not different than those in C57BL/6 wild-type mice. It has been suggested that PAF-AH (platelet-activating factor acetylhydrolase) increases susceptibility to vascular disease. Both LDb and LTp mice had significantly higher PAF-AH mRNA levels compared with C57BL/6 wild-type mice. PAF-AH gene expression was also significantly influenced by age and sex. Interestingly, PAF-AH mRNA levels were significantly higher in both LTp male and female mice than in the LDb mice. This increased PAF-AH gene expression was associated with elevated plasma PAF-AH enzyme activities (LTp>LDb>C57BL/6). Moreover, a greater proportion of PAF-AH activity was associated with the apoB-containing lipoproteins: 29% in LTp and 13% in LDb mice compared with C57BL/6 wild-type animals (6.7%). This may explain why LTp mice developed more atherosclerotic lesions than LDb mice by 8 months of age. In summary, increased plasma NEFAs, PAF-AH mRNA and enzyme activities are associated with accelerated atherogenesis in these animal models.

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 Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARα-mediated pathway

2001 ◽  
Vol 281 (6) ◽  
pp. E1197-E1204 ◽  
Author(s):  
Michael B. Armstrong ◽  
Howard C. Towle
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Oleic Acid ◽  
Polyunsaturated Fatty Acids ◽  
Uncoupling Protein ◽  
Protein S ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparα Agonist

The discovery of homologs of the brown fat uncoupling protein(s) (UCP) UCP-2 and UCP-3 revived the hypothesis of uncoupling protein involvement in the regulation of energy metabolism. Thus we hypothesized that UCP-2 would be regulated in the hepatocyte by fatty acids, which are known to control other energy-related metabolic processes. Treatment with 250 μM palmitic acid was without effect on UCP-2 expression, whereas 250 μM oleic acid exhibited a modest eightfold increase. Eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, exerted a 50-fold upregulation of UCP-2 that was concentration dependent. This effect was seen within 12 h and was maximal by 36 h. Aspirin blocked the induction of UCP-2 by EPA, indicating involvement of the prostaglandin pathway. Hepatocytes treated with arachidonic acid, the immediate precursor to the prostaglandins, also exhibited an aspirin-inhibitable increase in UCP-2 levels, further supporting the involvement of prostaglandins in regulating hepatic UCP-2. The peroxisome proliferator-activated receptor-α (PPARα) agonist Wy-14643 stimulated UCP-2 mRNA levels as effectively as EPA. These data indicate that UCP-2 is upregulated by polyunsaturated fatty acids, potentially through a prostaglandin/PPARα-mediated pathway.

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