Papers by Pieter de Lange
Faseb Journal, 2006
Coping with reduced energy sources entails drastic morphological and functional changes in skelet... more Coping with reduced energy sources entails drastic morphological and functional changes in skeletal muscle, but the sequence of events required classification. We found that gastrocnemius muscle from food-deprived rats shows acute rises in peroxisome proliferator activated receptor (PPAR) ␥ coactivator (PGC) -1␣/PPAR ␦ nuclear protein and myosin heavy chain (MHC) Ib protein, while type I fibers accumulate and the muscle tissue appears redder. AMP levels, phosphorylation of both AMP-activated protein kinase (AMPK) and its downstream target acetyl coenzyme A carboxylase (ACC) are induced within 6 h.
Thyroid, 2008
The processes and pathways mediating the intermediary metabolism of carbohydrates, lipids, and pr... more The processes and pathways mediating the intermediary metabolism of carbohydrates, lipids, and proteins are all affected by thyroid hormones (THs) in almost all tissues. Particular attention has been devoted by scientists to the effects of THs on lipid metabolism. Among others, effects related to cholesterol, lipid handling, and cardiac performance have been the subject of study. Many reports are present in the literature concerning the calorigenic effect of THs, with most of them aimed at identifying the molecular basis of this effect. However, at the moment the mechanism(s) underlying the metabolic effects of THs remain to be elucidated. THs exert most of their effects though TH receptors (TRs). However, some effects of THs cannot be explained by a nuclear-mediated pathway, and recently an increasing number of nonnuclear actions have been described, which can provide a regulatory system of which the effects differ from those mediated on the transcriptional level by TRs. Some of the TH derivatives (naturally occurring metabolites and analogs) possess biological activities. TH-related biological effects have been described for physiological products such as tetraiodothyroacetic acid (Tetrac) and triiodothyroacetic acid (Triac) (via oxidative deamination and decarboxylation of thyroxine [T4] and triiodothyronine [T3] alanine chain), 3,3',5'-triiodothyronine (rT3) (via T4 and T3 deiodination), 3,3'-diiodothyronine (3,3'-T2) and 3,5-diiodothyronine (T2) (via T4, T3, and rT3 deiodination), and 3-iodothyronamine (T1AM) and thyronamine (T0AM) (via T4 and T3 deiodination and amino acid decarboxylation), as well as for TH structural analogs, such as…
Journal of Cellular Physiology, 2008
Hamster (Mesocricetus auratus) harderian gland (HG) is a dimorphic orbital gland producing a copi... more Hamster (Mesocricetus auratus) harderian gland (HG) is a dimorphic orbital gland producing a copious lipid secretion. Two cell-types are present in hamster HG, type I in both sexes, type II only in males. In hamster HGs, we found a marked sexual dichotomy in the expression of uncoupling protein-3 (UCP3), a mitochondrial protein carrier, that probably exports fatty acid anions and fatty acid peroxides from the mitochondrial matrix. Following castration and/or testosterone treatment: (1) UCP3 levels correlated with the type II-cell percentage, not with testosterone levels, (2) in male HGs, UCP3 was comparable to female levels at 30 days post-castration (when the type II-cell percentage had fallen from 50 to 5%), although testosterone was already near zero at 15 days (when neither the type II-cell percentage nor the UCP3 level had fallen), and testosterone-replacement therapy prevented these changes. Testosterone-treated females possessed type II cells and a UCP3 level about twofold higher than in control females. Males displayed more intense UCP3 immunohistochemical positivity in type I HG cells than females. Hence, testosterone may indirectly control UCP3 expression by regulating the gland's morphological and lipid dimorphism. Straight-chain fatty acids [found in alkyl diacylglycerols (ADGs) in males] are oxidized predominantly in mitochondria, branched-chain fatty acids (abundant in ADGs in females) predominantly in peroxisomes, so we speculate that the higher UCP3 expression in males reflects greater fatty acid flux in HG mitochondria. This is supported by our finding that in female (not male) HGs, the peroxisome-rich fraction contained α-methylacyl-CoA racemase (AMACR), an enzyme important in the β-oxidation of branched-chain fatty acids. J. Cell. Physiol. 215: 481–487, 2008. © 2008 Wiley-Liss, Inc.
Journal of Hepatology, 2009
Background/Aims: Mitochondrial dysfunction is central to the physiopathology of steatosis and /or... more Background/Aims: Mitochondrial dysfunction is central to the physiopathology of steatosis and /or non-alcoholic fatty liver disease. In this study on rats we investigated whether 3,5-diiodo-L-thyronine (T2), a biologically active iodothyronine, acting at mitochondrial level is able to reverse hepatic steatosis after its induction through a high-fat diet.
Journal of Proteome Research, 2007
We analyzed the whole-cell protein content of gastrocnemius muscles from rats in different thyroi... more We analyzed the whole-cell protein content of gastrocnemius muscles from rats in different thyroid states. Twenty differentially expressed proteins were unambiguously identified. They were involved in substrates and energy metabolism, stress response, cell structure, and gene expression. This study represents the first systematic identification of thyroid state-induced changes in the skeletal muscle protein-expression profile and reveals new cellular pathways as targets for thyroid hormone action.
Pflugers Archiv-european Journal of Physiology, 2011
Controversy exists on whether uncoupling protein 3 (UCP3) positively or negatively influences ins... more Controversy exists on whether uncoupling protein 3 (UCP3) positively or negatively influences insulin sensitivity in vivo, and the underlying signaling pathways have been scarcely studied. We studied how a progressive reduction in UCP3 expression (using UCP3 +/+, UCP3 +/−, and UCP3 −/− mice) modulates insulin sensitivity and related metabolic parameters. In order to further validate our observations, we also studied animals in which insulin resistance was induced by administration of a high-fat diet (HFD). In UCP3 +/− and UCP3 −/− mice, gastrocnemius muscle Akt/protein kinase B (Akt/PKB) (serine 473) and AMP-activated protein kinase (AMPK) (threonine 171) phosphorylation, and glucose transporter 4 (GLUT4) membrane levels were reduced compared to UCP3 +/+ mice. The HOMA-IR index (insulin resistance parameter) was increased both in the UCP3 +/− and UCP3 −/− mice. In these mice, insulin administration normalized Akt/PKB phosphorylation between genotypes while AMPK phosphorylation was further reduced, and sarcolemmal GLUT4 levels were induced but did not reach control levels. Furthermore, non-insulin-stimulated muscle fatty acid oxidation and the expression of several involved genes both in muscle and in liver were reduced. HFD administration induced insulin resistance in UCP3 +/+ mice and the aforementioned parameters resulted similar to those of chow-fed UCP3 +/− and UCP3 −/− mice. In conclusion, high-fat-diet-induced insulin resistance in wild-type mice mimics that of chow-fed UCP3 +/− and UCP3 −/− mice showing that progressive reduction of UCP3 levels results in insulin resistance. This is accompanied by decreased fatty acid oxidation and a less intense Akt/PKB and AMPK signaling.
Biochimica Et Biophysica Acta-bioenergetics, 2010
Uncoupling proteins (UCPs) mediate proton conductance induced by fatty acid, stimulated by supero... more Uncoupling proteins (UCPs) mediate proton conductance induced by fatty acid, stimulated by superoxide and inhibited by GDP. At the same time, mitochondrial adenine nucleotide translocase (ANT) also is able to transport fatty acid anions, and uncouple oxidation and phosphorylation. In present work an attempt was made to reveal protonophore activity of UCP2 and UCP3, using inhibitory effect of GDP (generally considered specific for UCPs) and carboxyatractylate (cAtr), considered specific for ANT. Skeletal muscle mitochondria of Yakutian hibernating ground squirrels were chosen basing on significant level of UCP3 mRNA. Rat kidney and liver mitochondria were chosen as objects, since literature data indicate the activation of UCP2 by superoxide in kidney unlikely to liver. We found that GDP in millimolar concentrations had a slight recoupling effect on respiration rate and membrane potential in skeletal muscle mitochondria of hibernating animals. GDP had no effect, if cAtr in micromolar concentration was added previously. Moreover, GDP and ADP demonstrated competitive kinetic relative to ANT. Evaluated parameters of kinetics revealed affinity to ANT decreasing in order: ADP>GDP>UDP>CDP. Skeletal muscle mitochondria failed to show chloride permeability unlikely to brown fat mitochondria. In brown fat cAtr was not able to prevent UCP1iduced chloride permeability, and inhibitory effect of GDP. Superoxide increased the initial respiration rate, decreased the maximal respiration velocity and membrane potential in kidney. Slow decrease of respiration rate and restoration of membrane potential were observed after addition of ADP or GDP, being intensified upon subsequent treatment by cAtr. However, addition of ADP or GDP after cAtr had no effect on recoupling of respiration, even in the presence of superoxide. No crucial differences were found in kidney and liver mitochondria. Evaluation of the mRNA level for UCP2 and ANT genes indicates that the expression of UCP2 mRNA in kidney was even lower than in liver mitochondria. The stronger effect of ADP in kidney apparently is correlated with a higher level of ANT. The data obtained allow us to conclude that recoupling effect of purine nucleotides both in the presence and in the absence of superoxide in the mitochondria of rat liver and kidneys, and skeletal muscle mitochondria of hibernating ground squirrels may be explained by their interaction with ANT rather than by functioning of UCP2 and UCP3.
Faseb Journal, 2007
Energy deprivation poses a tremendous challenge to skeletal muscle. Glucose (ATP) depletion cause... more Energy deprivation poses a tremendous challenge to skeletal muscle. Glucose (ATP) depletion causes muscle fibers to undergo rapid adaptive changes toward the use of fatty acids (instead of glucose) as fuel. Physiological situations involving energy deprivation in skeletal muscle include exercise and fasting. A vast body of evidence is available on the signaling pathways that lead to structural/metabolic changes in muscle during exercise and endurance training. In contrast, only recently has a systematic, overall picture been obtained of the signaling processes (and their kinetics and sequential order) that lead to adaptations of the muscle to the fasting state. It has become clear that the reaction of the organism to food restraint or deprivation involves a rapid signaling process causing skeletal muscles, which generally use glucose as their predominant fuel, to switch to the use of fat as fuel. Efficient sensing of glucose depletion in skeletal muscle guarantees maintained activity in those tissues that rely entirely on glucose (such as the brain). To metabolize fatty acids, skeletal muscle needs to activate complex transcription, translation, and phosphorylation pathways. Only recently has it become clear that these pathways are interrelated and tightly regulated in a rapid, transient manner. Food deprivation may trigger these responses with a timing/intensity that differs among animal species and that may depend on their individual ability to induce structural/metabolic changes that serve to safeguard whole-body energy homeostasis in the longer term. The increased cellular AMP/ATP ratio induced by food deprivation, which results in activation of AMP-activated protein kinase (AMPK), initiates a rapid signaling process, resulting in the recruitment of factors mediating the structural/ metabolic shift in skeletal muscle toward this change in fuel usage. These factors include peroxisome proliferator-activated receptor (PPAR)␥ coactivator-1␣ (PGC-1␣), PPAR␦, and their target genes, which are involved in the formation of oxidative muscle fibers, mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation. Fatty acids, besides being the fuel for mitochondrial oxidation, have been identified as important signaling molecules regulating the transcription and/or activity of the genes or gene products involved in fatty acid metabolism during food deprivation. It is thus becoming increasingly clear that fatty acids determine the economy of their own usage. We discuss the order of events from the onset of food deprivation and their importance.-de Lange, P., Moreno, M., Silvestri, E., Lombardi, A., Goglia, F., Lanni, A. Fuel economy in food-deprived skeletal muscle: signaling pathways and regulatory mechanisms. FASEB J. 21, 3431-3441
Journal of Proteome Research, 2006
We analyzed whole cell protein content of rat liver following T3 administration. Fourteen differe... more We analyzed whole cell protein content of rat liver following T3 administration. Fourteen differentially expressed proteins were unambiguously identified and were involved in substrates and lipid metabolism, energy metabolism, detoxification of cytotoxic products, calcium homeostasis, amino acid catabolism, and the urea cycle. This study represents the first systematic identification of T3-induced changes in liver protein expression profile and provides novel information at the molecular, cellular, and tissue level of T3 action.
Faseb Journal, 2006
Coping with reduced energy sources entails drastic morphological and functional changes in skelet... more Coping with reduced energy sources entails drastic morphological and functional changes in skeletal muscle, but the sequence of events required classification. We found that gastrocnemius muscle from food-deprived rats shows acute rises in peroxisome proliferator activated receptor (PPAR) ␥ coactivator (PGC) -1␣/PPAR ␦ nuclear protein and myosin heavy chain (MHC) Ib protein, while type I fibers accumulate and the muscle tissue appears redder. AMP levels, phosphorylation of both AMP-activated protein kinase (AMPK) and its downstream target acetyl coenzyme A carboxylase (ACC) are induced within 6 h.
Ppar Research, 2008
Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have... more Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPARdelta induces cell proliferation through a novel cyclin E1-dependent mechanism and is up-regulated in many human thyroid tumors. The expression of PPARdelta was induced coordinately with proliferation in primary human thyroid cells by the activation of serum, thyroid-stimulating hormone/cyclic AMP, or epidermal growth factor/mitogen-activated protein kinase mitogenic signaling pathways. Engineered overexpression of PPARdelta increased thyroid cell number, the incorporation of bromodeoxyuridine, and the phosphorylation of retinoblastoma protein by 40% to 45% in just 2 days, one usual cell population doubling. The synthetic PPARdelta agonist GW501516 augmented these PPARdelta proliferation effects in a dose-dependent manner. Overexpression of PPARdelta increased cyclin E1 protein by 9-fold, whereas knockdown of PPARdelta by small inhibitory RNA reduced both cyclin E1 protein and cell proliferation by 2-fold. Induction of proliferation by PPARdelta was abrogated by knockdown of cyclin E1 by small inhibitory RNA in primary thyroid cells and by knockout of cyclin E1 in mouse embryo fibroblasts, confirming a cyclin E1 dependence for this PPARdelta pathway. In addition, the mean expression of native PPARdelta was increased by 2-fold to 5-fold (P < 0.0001) and correlated with that of the in situ proliferation marker Ki67 (R = 0.8571; P = 0.02381) in six different classes of benign and malignant human thyroid tumors. Our experiments identify a PPARdelta mechanism that induces cell proliferation through cyclin E1 and is regulated by growth factor and lipid signals. The data argue for systematic investigation of PPARdelta antagonists as antineoplastic agents and implicate altered PPARdelta-cyclin E1 signaling in thyroid and other carcinomas.
Thyroid, 2008
The processes and pathways mediating the intermediary metabolism of carbohydrates, lipids, and pr... more The processes and pathways mediating the intermediary metabolism of carbohydrates, lipids, and proteins are all affected by thyroid hormones (THs) in almost all tissues. Particular attention has been devoted by scientists to the effects of THs on lipid metabolism. Among others, effects related to cholesterol, lipid handling, and cardiac performance have been the subject of study. Many reports are present in the literature concerning the calorigenic effect of THs, with most of them aimed at identifying the molecular basis of this effect. However, at the moment the mechanism(s) underlying the metabolic effects of THs remain to be elucidated. THs exert most of their effects though TH receptors (TRs). However, some effects of THs cannot be explained by a nuclear-mediated pathway, and recently an increasing number of nonnuclear actions have been described, which can provide a regulatory system of which the effects differ from those mediated on the transcriptional level by TRs. Some of the TH derivatives (naturally occurring metabolites and analogs) possess biological activities. TH-related biological effects have been described for physiological products such as tetraiodothyroacetic acid (Tetrac) and triiodothyroacetic acid (Triac) (via oxidative deamination and decarboxylation of thyroxine [T4] and triiodothyronine [T3] alanine chain), 3,3',5'-triiodothyronine (rT3) (via T4 and T3 deiodination), 3,3'-diiodothyronine (3,3'-T2) and 3,5-diiodothyronine (T2) (via T4, T3, and rT3 deiodination), and 3-iodothyronamine (T1AM) and thyronamine (T0AM) (via T4 and T3 deiodination and amino acid decarboxylation), as well as for TH structural analogs, such as…
Faseb Journal, 2005
The effect of thyroid hormones on metabolism has long supported their potential as drugs to stimu... more The effect of thyroid hormones on metabolism has long supported their potential as drugs to stimulate fat reduction, but the concomitant induction of a thyrotoxic state has greatly limited their use. Recent evidence suggests that 3,5-diiodo-L-thyronine (T 2 ), a naturally occurring iodothyronine, stimulates metabolic rate via mechanisms involving the mitochondrial apparatus. We examined whether this effect would result in reduced energy storage. Here, we show that T 2 administration to rats receiving a high-fat diet (HFD) reduces both adiposity and body weight gain without inducing thyrotoxicity. Rats receiving HFD + T 2 showed (when compared with rats receiving HFD alone) a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, ~50% less fat mass, a complete disappearance of fat from the liver, and significant reductions in the serum triglyceride and cholesterol levels (-52% and -18%, respectively). Thyroid hormones and thyroid-stimulating hormone (TSH) serum levels were not influenced by T 2 administration. The biochemical mechanism underlying the effects of T 2 on liver metabolism involves the carnitine palmitoyl-transferase system and mitochondrial uncoupling. If the results hold true for humans, pharmacological administration of T 2 might serve to counteract the problems associated with overweight, such as accumulation of lipids in liver and serum, without inducing thyrotoxicity. However, the results reported here do not exclude deleterious effects of T 2 on a longer time scale as well as do not show that T 2 acts in the same way in humans.
Ppar Research, 2010
Peroxisome proliferator-activated receptors (PPARs), which are known to regulate lipid homeostasi... more Peroxisome proliferator-activated receptors (PPARs), which are known to regulate lipid homeostasis, are tightly controlled by nutrient availability, and they control nutrient handling. In this paper, we focus on how nutrients control the expression and action of PPARs and how cellular signaling events regulate the action of PPARs in metabolically active tissues (e.g., liver, skeletal muscle, heart, and white adipose tissue). We address the structure and function of the PPARs, and their interaction with other nuclear receptors, including PPAR cross-talk. We further discuss the roles played by different kinase pathways, including the extracellular signal-regulated kinases/mitogen-activated protein kinase (ERK MAPK), AMP-activated protein kinase (AMPK), Akt/protein kinase B (Akt/PKB), and the NAD+-regulated protein deacetylase SIRT1, serving to control the activity of the PPARs themselves as well as that of a key nutrient-related PPAR coactivator, PPARγ coactivator-1α (PGC-1α). We also highlight how currently applied nutrigenomic strategies will increase our understanding on how nutrients regulate metabolic homeostasis through PPAR signaling.
Thyroid hormones increase energy expenditure, partly by reducing metabolic efficiency. The contro... more Thyroid hormones increase energy expenditure, partly by reducing metabolic efficiency. The control of specific genes at the transcriptional level is thought to be the major molecular mechanism. However, both the number and the identity of the thyroid hormone-controlled genes remain unknown, as do their relative contributions. Uncoupling protein-3, a recently identified member of the mitochondrial transporter superfamily and one that is predominantly expressed in skeletal muscle, has the potential to be a molecular determinant for thyroid thermogenesis. However, changes in mitochondrial proton conductance and resting metabolic rate after physiologically mediated changes in uncoupling protein-3 levels have not been described. Here, in a study on hypothyroid rats given a single injection of T 3 , we describe a strict correlation in terms of time course between the induced increase in uncoupling protein-3 expression (at mRNA and protein levels) and decrease in mitochondrial respiratory efficiency, on the one hand, and the increase in resting metabolic rate, on the other. First, we describe our finding that uncoupling protein-3 is present and regulated by T 3 only in metabolically relevant tissues (such as skeletal muscle and heart). Second, we follow the time course (at 0, 6, 12, 24, 48, 65, 96, and 144 h) of both uncoupling protein-3 mRNA levels and mitochondrial uncoupling protein-3 density in gastrocnemius muscle and heart. In both tissues, the maximal (12-fold) increase in uncoupling protein-3 density was reached at 65 h. The resting metabolic rate [lO 2 (kg 0.75 ) ؊1 h ؊1 ] showed the same time course, and at 65 h the increase vs. time zero was 45% (1.316 ؎ 0.026 vs. 0.940 ؎ 0.007; P < 0.001). At the same time point, gastrocnemius muscle mitochondria showed a significantly higher nonphosphorylating respiration rate (nanoatoms of oxygen per min/mg protein; increase vs. time zero, 40%; 118 ؎ 4 vs. 85 ؎ 9; P < 0.05), whereas the membrane potential decreased by 8% (168 ؎ 2 vs. 182 ؎ 4; P < 0.05). These data are diagnostic of mitochondrial uncoupling. The results reported here provide the first direct in vivo evidence that uncoupling protein-3 has the potential to act as a molecular determinant in the regulation of resting metabolic rate by T 3 . (Endocrinology 142: 3414 -3420, 2001)
Journal of Cellular Physiology, 2008
Hamster (Mesocricetus auratus) harderian gland (HG) is a dimorphic orbital gland producing a copi... more Hamster (Mesocricetus auratus) harderian gland (HG) is a dimorphic orbital gland producing a copious lipid secretion. Two cell-types are present in hamster HG, type I in both sexes, type II only in males. In hamster HGs, we found a marked sexual dichotomy in the expression of uncoupling protein-3 (UCP3), a mitochondrial protein carrier, that probably exports fatty acid anions and fatty acid peroxides from the mitochondrial matrix. Following castration and/or testosterone treatment: (1) UCP3 levels correlated with the type II-cell percentage, not with testosterone levels, (2) in male HGs, UCP3 was comparable to female levels at 30 days post-castration (when the type II-cell percentage had fallen from 50 to 5%), although testosterone was already near zero at 15 days (when neither the type II-cell percentage nor the UCP3 level had fallen), and testosterone-replacement therapy prevented these changes. Testosterone-treated females possessed type II cells and a UCP3 level about twofold higher than in control females. Males displayed more intense UCP3 immunohistochemical positivity in type I HG cells than females. Hence, testosterone may indirectly control UCP3 expression by regulating the gland's morphological and lipid dimorphism. Straight-chain fatty acids [found in alkyl diacylglycerols (ADGs) in males] are oxidized predominantly in mitochondria, branched-chain fatty acids (abundant in ADGs in females) predominantly in peroxisomes, so we speculate that the higher UCP3 expression in males reflects greater fatty acid flux in HG mitochondria. This is supported by our finding that in female (not male) HGs, the peroxisome-rich fraction contained α-methylacyl-CoA racemase (AMACR), an enzyme important in the β-oxidation of branched-chain fatty acids. J. Cell. Physiol. 215: 481–487, 2008. © 2008 Wiley-Liss, Inc.
Biochimica Et Biophysica Acta-bioenergetics, 2006
Fibrates (anti-hyperlipidemic agents) enhance the mRNA expression of uncoupling protein 2 (UCP2) ... more Fibrates (anti-hyperlipidemic agents) enhance the mRNA expression of uncoupling protein 2 (UCP2) in the liver and that of uncoupling protein 3 (UCP3) in skeletal muscle in standard-diet-fed rats and induce a de novo expression of UCP3 (mRNA and protein) in the liver of high-fat-fed rats. Here, we report that in the liver of normal rats, fenofibrate induces a de novo expression of UCP3 and a 6-fold increase in UCP2 mRNA, whereas UCP2 protein was not detectable. Indeed, we evidenced an ORF in UCP2 exon 2 potentially able to inhibit the expression of the protein. Fenofibrate increases the expression and activity of hepatic enzymes and cofactors involved in lipid handling and UCP3 activity and, as is the case for UCP3, induces other muscle-specific genes (e.g., Carnitine palmitoyl transferase 1b and Ubiquinone biosynthesis protein COQ7 homolog). In addition, we demonstrated that in mitochondria from fenofibrate-treated rats a palmitoyl-carnitineinduced GDP-sensitive uncoupling takes place, involving UCP3 rather than other uncouplers (i.e., UCP2 and Adenine Nucleotide Translocase). Thus, the liver of fenofibrate-treated standard-diet-fed rat is a useful model for investigations of the biochemical functions of UCP3 and allowed us to demonstrate that fenofibrate programs a gene-expression pattern able to modulate lipid handling and UCP3 activation.
Journal of Hepatology, 2009
Background/Aims: Mitochondrial dysfunction is central to the physiopathology of steatosis and /or... more Background/Aims: Mitochondrial dysfunction is central to the physiopathology of steatosis and /or non-alcoholic fatty liver disease. In this study on rats we investigated whether 3,5-diiodo-L-thyronine (T2), a biologically active iodothyronine, acting at mitochondrial level is able to reverse hepatic steatosis after its induction through a high-fat diet.
Biofactors, 2009
Since their discovery, uncoupling proteins have aroused great interest due to the crucial importa... more Since their discovery, uncoupling proteins have aroused great interest due to the crucial importance of energy-dissipating system for cellular physiology. The uncoupling effect and the physiological role of UCP1 (the first-described uncoupling protein) are well established. However, the reactions catalyzed by UCP1 homologues (UCPs), and their physiological roles are still under debate, with the literature containing contrasting results. Current hypothesis propose several physiological functions for novel UCPs, such as: (i) attenuation of reactive oxygen species production and protection against oxidative damage, (ii) thermogenic function, although UCPs do not generally seem to affect thermogenesis, UCP3 can be thermogenic under certain conditions, (iii) involvement in fatty acid handling and/or transport, although recent experimental evidence argues against the previously hypothesized role for UCPs in the export of fatty acid anions, (iv) fatty acid hydroperoxide export, although this function, due to the paucity of the experimental evidence, remains hypothetical, (v) Ca2+ uptake, although results for and against a role in Ca2+ uptake are still emerging, (vi) a signaling role in pancreatic beta cells, where it attenuates glucose-induced insulin secretion. From the above, it is evident that more research will be needed to establish universally accepted functions for UCPs. © 2009 International Union of Biochemistry and Molecular Biology, Inc.
Journal of Proteome Research, 2007
We analyzed the whole-cell protein content of gastrocnemius muscles from rats in different thyroi... more We analyzed the whole-cell protein content of gastrocnemius muscles from rats in different thyroid states. Twenty differentially expressed proteins were unambiguously identified. They were involved in substrates and energy metabolism, stress response, cell structure, and gene expression. This study represents the first systematic identification of thyroid state-induced changes in the skeletal muscle protein-expression profile and reveals new cellular pathways as targets for thyroid hormone action.
Uploads
Papers by Pieter de Lange