scholarly journals Thyroid hormones directly activate the expression of the human and mouse uncoupling protein-3 genes through a thyroid response element in the proximal promoter region

2005 ◽  
Vol 386 (3) ◽  
pp. 505-513 ◽  
Author(s):  
Gemma SOLANES ◽  
Neus PEDRAZA ◽  
Verónica CALVO ◽  
Antonio VIDAL-PUIG ◽  
Bradford B. LOWELL ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Uncoupling Protein ◽  
Gene Promoter ◽  
Proximal Promoter ◽  
Ucp3 Gene ◽  
Uncoupling Protein 3

The transcription of the human UCP3 (uncoupling protein-3) gene in skeletal muscle is tightly regulated by metabolic signals related to fatty acid availability. However, changes in thyroid status also modulate UCP3 gene expression, albeit by unknown mechanisms. We created transgenic mice bearing the entire human UCP3 gene to investigate the effect of thyroid hormones on human UCP3 gene expression. Treatment of human UCP3 transgenic mice with thyroid hormones induced the expression of the human gene in skeletal muscle. In addition, transient transfection experiments demonstrate that thyroid hormones activate the transcription of the human UCP3 gene promoter when MyoD and the TR (thyroid hormone receptor) were co-transfected. The action of thyroid hormones on UCP3 gene transcription is mediated by the binding of the TR to a proximal region in the UCP3 gene promoter that contains a direct repeat structure. An intact DNA sequence of this site is required for thyroid hormone responsiveness and TR binding. Chromatin immunoprecipitation assays revealed that the TR binds this element in vivo. The murine Ucp3 gene promoter was also dependent on MyoD and responsive to thyroid hormone in transient transfection assays. However, it was much less sensitive to thyroid hormone than the human UCP3 promoter. In summary, UCP3 gene transcription is activated by thyroid hormone treatment in vivo, and this activation is mediated by a TRE (thyroid hormone response element) in the proximal promoter region. Such regulation suggests a link between UCP3 gene expression and the effects of thyroid hormone on mitochondrial function in skeletal muscle.

scholarly journals Developmental and Tissue-Specific Involvement of Peroxisome Proliferator-Activated Receptor-α in the Control of Mouse Uncoupling Protein-3 Gene Expression

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4695-4704 ◽  
Author(s):  
Neus Pedraza ◽  
Meritxell Rosell ◽  
Joan Villarroya ◽  
Roser Iglesias ◽  
Frank J. Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Mrna Expression ◽  
Uncoupling Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ucp3 Gene ◽  
Uncoupling Protein 3

Uncoupling protein-3 (UCP3) is a member of the mitochondrial carrier family expressed preferentially in skeletal muscle and heart. It appears to be involved in metabolic handling of fatty acids in a way that minimizes excessive production of reactive oxygen species. Fatty acids are powerful regulators of UCP3 gene transcription. We have found that the role of peroxisome proliferator-activated receptor-α (PPARα) on the control of UCP3 gene expression depends on the tissue and developmental stage. In adults, UCP3 mRNA expression is unaltered in skeletal muscle from PPARα-null mice both in basal conditions and under the stimulus of starvation. In contrast, UCP3 mRNA is down-regulated in adult heart both in fed and fasted PPARα-null mice. This occurs despite the increased levels of free fatty acids caused by fasting in PPARα-null mice. In neonates, PPARα-null mice show impaired UCP3 mRNA expression in skeletal muscle in response to milk intake, and this is not a result of reduced free fatty acid levels. The murine UCP3 promoter is activated by fatty acids through either PPARα or PPARδ but not by PPARγ or retinoid X receptor alone. PPARδ-dependent activation could be a potential compensatory mechanism to ensure appropriate expression of UCP3 gene in adult skeletal muscle in the absence of PPARα. However, among transcripts from other PPARα and PPARδ target genes, only those acutely induced by milk intake in wild-type neonates were altered in muscle or heart from PPARα-null neonates. Thus, PPARα-dependent regulation is required for appropriate gene regulation of UCP3 as part of the subset of fatty-acid-responsive genes in neonatal muscle and heart.

Effect of Thyroid Hormone on Uncoupling Protein-3 mRNA Expression in Rat Heart and Skeletal Muscle

Thyroid ◽  
2004 ◽  
Vol 14 (3) ◽  
pp. 177-185 ◽  
Author(s):  
Marcia Silva Queiroz ◽  
Yvonne Shao ◽  
Faramarz Ismail-Beigi
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Mrna Expression ◽  
Rat Heart ◽  
Uncoupling Protein ◽  
Uncoupling Protein 3

scholarly journals Thyroid hormone receptors are down-regulated in skeletal muscle of patients with non-thyroidal illness syndrome secondary to non-septic shock

2010 ◽  
Vol 163 (5) ◽  
pp. 765-773 ◽  
Author(s):  
J Lado-Abeal ◽  
A Romero ◽  
I Castro-Piedras ◽  
A Rodriguez-Perez ◽  
J Alvarez-Escudero
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Septic Shock ◽  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Serum Samples ◽  
Pathway Activation ◽  
Gene And Protein Expression

AimNon-thyroidal illness syndrome (NTIS) is related to changes in thyroid hormone (TH) physiology. Skeletal muscle (SM) plays a major role in metabolism, and TH regulates SM phenotype and metabolism. We aimed to characterize the SM of non-septic shock NTIS patients in terms of: i) expression of genes and proteins involved in TH metabolism and actions; and ii) NFKB's pathway activation, a responsible factor for some of the phenotypic changes in NTIS. We also investigated whether the patient's serum can induce in vitro the effects observed in vivo.MethodsSerum samples and SM biopsies from 14 patients with non-septic shock NTIS and 11 controls. Gene and protein expression and NFKB1 activation were analyzed by quantitative PCR and immunoblotting. Human SM cell (HSkMC) cultures to investigate the effects of patient's serum on TH action mediators.ResultsPatients with non-septic shock NTIS showed higher levels of pro-inflammatory cytokines than controls. Expression of TRβ (THRB), TRα1 (THRA), and retinoid X receptor γ (RXRG) was decreased in NTIS patients. RXRA gene expression was higher, but its protein was lower in NTIS than controls, suggesting the existence of a post-transcriptional mechanism that down-regulates protein levels. NFKB1 pathway activation was not different between NTIS and control patients. HSkMC incubated with patient's serum increased TH receptor and RXRG gene expression after 48 h.ConclusionsPatients with non-septic shock NTIS showed decreased expression of TH receptors and RXRs, which were not related to increased activation of the NFKB1 pathway. These findings could not be replicated in cultures of HSkMCs incubated in the patient's serum.

scholarly journals Uncoupling protein 2 and 3 in marsupials: identification, phylogeny, and gene expression in response to cold and fasting in Antechinus flavipes

2004 ◽  
Vol 17 (2) ◽  
pp. 130-139 ◽  
Author(s):  
Martin Jastroch ◽  
Kerry Withers ◽  
Martin Klingenspor
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Tissue Specificity ◽  
Striated Muscle ◽  
Uncoupling Protein ◽  
Uncoupling Protein 2 ◽  
Reading Frame ◽  
Amino Acid Peptide ◽  
Ucp3 Gene

We searched for the presence of uncoupling protein genes so far unknown in marsupials and monotremes and identified uncoupling protein 2 (UCP2) and UCP3 full-length cDNAs in libraries constructed from the marsupials Antechinus flavipes and Sminthopsis macroura. Marsupial UCP2 is 89–90% identical to rodent UCP2, whereas UCP3 exhibits 80% identity to mouse UCP3. A phylogenetic tree including all known UCPs positions the novel marsupial UCP2 and UCP3 at the base of the mammalian orthologs. In the 5′-untranslated region of UCP2 a second open reading frame encoding for a 36-amino acid peptide was identified which is highly conserved in all vertebrate UCP2 transcripts. Analysis of tissue specificity in A. flavipes with homologous cDNA probes revealed ubiquitous presence of UCP2 mRNA and striated muscle specificity of UCP3 mRNA resembling the known expression pattern in rodents. Neither UCP2 nor UCP3 gene expression was stimulated in adipose tissue and skeletal muscle of cold exposed A. flavipes. However, UCP3 mRNA expression was upregulated 6-fold in heart and 2.5-fold in skeletal muscle as reported for rodents in response to fasting. Furthermore, UCP3 mRNA seems to be coregulated with PDK4 mRNA, indicating a relation to enhanced lipid metabolism. In contrast, UCP2 gene expression was not regulated in response to fasting in adipose tissue and skeletal muscle but was diminished in the lung and increased in adipose tissue. Taken together, the sequence analysis, tissue specificity and physiological regulation suggest a conserved function of UCP2 and UCP3 during 130 million years of mammalian evolution.

scholarly journals Uncoupling protein-3 gene expression: reduced skeletal muscle mRNA in obese humans during pronounced weight loss

Diabetologia ◽  
1999 ◽  
Vol 42 (3) ◽  
pp. 302-309 ◽  
Author(s):  
H. Esterbauer ◽  
H. Oberkofler ◽  
G. Dallinger ◽  
D. Breban ◽  
E. Hell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Weight Loss ◽  
Uncoupling Protein ◽  
Uncoupling Protein 3

scholarly journals Oxidative damage and phospholipid fatty acyl composition in skeletal muscle mitochondria from mice underexpressing or overexpressing uncoupling protein 3

2002 ◽  
Vol 368 (2) ◽  
pp. 597-603 ◽  
Author(s):  
Martin D. BRAND ◽  
Reinald PAMPLONA ◽  
Manuel PORTERO-OTÍN ◽  
Jesús R. REQUENA ◽  
Stephen J. ROEBUCK ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Damage ◽  
Uncoupling Protein ◽  
Fatty Acyl ◽  
Proton Conductance ◽  
Acyl Composition ◽  
Skeletal Muscle Mitochondria ◽  
Fatty Acyl Composition ◽  
Uncoupling Protein 3

Five markers of different kinds of oxidative damage to proteins [glutamic semialdehyde, aminoadipic semialdehyde, N∊-(carboxymethyl)lysine, N∊-(carboxyethyl)lysine and N∊-(malondialdehyde)lysine] and phospholipid fatty acyl composition were identified and measured in skeletal muscle mitochondria isolated from mice genetically engineered to underexpress or overexpress uncoupling protein 3 (UCP3). Mitochondria from UCP3-underexpressing mice had significantly higher levels of oxidative damage than wild-type controls, suggesting that UCP3 functions in vivo as part of the antioxidant defences of the cell, but mitochondria from UCP3-overexpressing mice had unaltered oxidative damage, suggesting that mild uncoupling in vivo beyond the normal basal uncoupling provides little protection against oxidative stress. Mitochondria from UCP3-underexpressing mice showed little change, but mitochondria from UCP3-overexpressing mice showed marked changes in mitochondrial phospholipid fatty acyl composition. These changes were very similar to those previously found to correlate with basal proton conductance in mitochondria from a range of species and treatments, suggesting that high protein expression, or some secondary result of uncoupling, may cause the observed correlation between basal proton conductance and phospholipid fatty acyl composition.

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