ABSTRACT
Thyroid dysfunction and dementia are conditions that become more prevalent with advancing age. Localised hypothyroidism of the central nervous system has been sugested in some patients with Alzheimer's disease. We investigated the consequence of adult-onset hypothyroidism on beta-amyloid precursor protein (APP) degrading pathways in rats treated with propylthiouracyl over a period of 5 weeks. We evaluated the amount of 3,5,3'-triiodothyronine nuclear receptors (TRalpha1 and TRbeta) and the expression of some APP processing indicators (i.e. APP, ADAM 10, BACE and PS1). The activity of secretases and Abeta peptides has been also quantified. The results obtained show that hypoactivity of the thyroid signalling pathway in the hippocampus induced an increase in the APP770-751/APP695 ratio accompanied by a modification in the amyloidogenic pathway for APP processing, leading to an increased amount of Abeta peptides. In this area of the brain, modification in the non-amyloidogenic pathway of APP processing characterised by alpha-secretase activity was only approximately 10% in hypothyroid rats compared to control rats. We suggest that hypothyroidism, which becomes more prevalent with advancing age, increased the vulnerability to the formation of amyloid deposits.
Subject(s)
Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Hippocampus/metabolism , Hypothyroidism/metabolism , Adult , Amyloid Precursor Protein Secretases/genetics , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Cerebral Cortex/metabolism , Humans , Protein Isoforms/genetics , Protein Isoforms/metabolism , Random Allocation , Rats , Rats, Wistar , Signal Transduction/physiology , Thyroid Hormone Receptors alpha/metabolism , Thyroid Hormone Receptors beta/metabolismABSTRACT
In order to evaluate the expression of nuclear receptors at the peripheral level in obese subjects, messenger RNA (mRNA) levels of different isoforms of retinoic acid receptor (RAR), triiodothyronine (TR), and peroxisome proliferator-activated receptor (PPAR) were determined and compared in peripheral mononuclear blood cells (PBMC) and subcutaneous white adipose tissue (SWAT). Twelve lean subjects and 68 obese subjects divided into weight gain (WG), weight-stable (WS), and weight loss (WL) groups were studied. Nuclear receptor mRNA levels were assessed in PBMC and SWAT using a quantitative real-time reverse transcription polymerase chain reaction method. mRNA levels of RARgamma were significantly lower in PBMC of obese subjects (WG -19%, WS -30%, and WL -24.7%) as in SWAT of WG (-50%). Lower mRNA levels of TRbeta were observed in PBMC and SWAT of WG (-50.7% and -28%, respectively) just as for TRalpha in PBMC of WG (-19%). In contrast, retinoid X receptors alpha (RXRalpha) and RARalpha mRNA levels were higher in PBMC of obese subjects (+53% and +54.5% in WG, +56% and +67% in WS, and +68% and +49.7% in WL, respectively), while expression of RXRalpha was lower in SWAT of WG (-24.5%). As for PPARgamma, its mRNA level was significantly higher in PBMC of WG subjects (+34%) while its expression was not modified in SWAT, contrary to the PPARgamma2 isoform which was significantly higher. These data show that in both adipose tissue and blood compartment of obese subjects, expressions of RARgamma and TRbeta were downregulated. Thus, we suggest that the expression in PBMC of obese subjects may constitute new cellular indicators of nuclear receptor retinoid and thyroid status.
Subject(s)
Leukocytes, Mononuclear/metabolism , Obesity/genetics , Receptors, Retinoic Acid/genetics , Subcutaneous Fat/metabolism , Triiodothyronine/genetics , Weight Gain/genetics , Adult , Humans , Middle Aged , Obesity/metabolism , RNA, Messenger/metabolism , Receptors, Retinoic Acid/metabolism , Triiodothyronine/metabolism , Retinoic Acid Receptor gammaABSTRACT
No disponible
In order to evaluate the expression of nuclear receptors at the peripheral level in obese subjects,messenger RNA (mRNA) levels of different isoforms of retinoic acid receptor (RAR), triiodothyronine(TR), and peroxisome proliferator-activated receptor (PPAR) were determined and compared in peripheral mononuclear blood cells (PBMC) and subcutaneous white adipose tissue (SWAT). Twelve lean subjects and 68 obese subjects divided into weight gain (WG), weight-stable (WS), and weight loss (WL) groups were studied. Nuclear receptor mRNA levels were assessed in PBMC and SWAT using a quantitative real-time reverse transcription polymerase chain (..) (AU)
Subject(s)
Humans , Leukocytes, Mononuclear , Obesity/genetics , RNA, Messenger/analysis , Receptors, Retinoic Acid/analysis , Triiodothyronine/analysis , Peroxisome Proliferator-Activated Receptors/analysis , Subcutaneous Fat , Thyroid HormonesABSTRACT
AIMS: In type 2 diabetes (T2D), insulin-induced weight gain may stem from a reduction in resting energy expenditure (REE). We sought to determine the early effects of insulin introduction on REE in 20 poorly controlled T2D patients. METHODS: After improving the glycaemia, REE was measured on Day 0 and Day 4 during two treatment regimens: bedtime insulin (n=10, group 1); and one off (3-day) intravenous insulin infusion (n=10, group 2). RESULTS: Both groups were similar in age, gender, BMI, C-peptide, HbA(1c) and initial REE. By Day 4, fasting glycaemia had similarly improved in both groups: group 1: -5.3+/-2.7mmol/L vs group 2: -5.8+/-4.2 mmol/L. In group 2, the second REE was measured 12h after stopping the intravenous insulin infusion, whereas subcutaneous insulin was maintained in group 1. REE did not change in group 2 (-1.3+/-6.5%), whereas it decreased significantly in group 1 (-8.0+/-7.0%; P<0.05). CONCLUSION: Bedtime insulin led to an early and specific reduction in REE.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Energy Metabolism/physiology , Insulin/administration & dosage , Adult , Aged , Blood Glucose/analysis , Body Mass Index , C-Peptide/blood , Female , Glycated Hemoglobin/analysis , Humans , Infusions, Intravenous , Injections, Subcutaneous , Insulin/analogs & derivatives , Insulin/therapeutic use , Male , Middle Aged , Respiration , Rest , Statistics, Nonparametric , Time Factors , Weight Gain/drug effectsABSTRACT
Thyroid hormone (TH) deficiency leads to molecular changes resulting in behavioural deficits. TH action is mediated by two types of nuclear receptors (TRs), TRalpha and TRbeta, which control target gene transcription. The relative contributions of the two TR products in mediating adult TH responses are poorly understood. As TRalpha1 transcripts are widely distributed in the brain, they presumably mediate most of the TH effects. This report examines the role and specific functions of T3 receptor isoforms on regulation of striatal synaptic plasticity indicators using adult hypothyroid mutant mice that fail to express single or multiple TR gene products. We then evaluated the effect of this hypothyroidism, with or without subsequent administration of T3, on T3 nuclear receptor (TRalpha1, TRbeta) and synaptic plasticity gene expression in TRalpha(0/0), TRbeta(-/-) and wild-type 129/SV mice. Hypothyroid wild-type mice exhibited reduced TRbeta, RC3, CaMKII and Rhes expression. The mRNA levels of Rhes and CaMKII were the same in all three hypothyroid substrains. By contrast, hypothyroid TRbeta(-/-) mice had higher RC3 mRNA levels than wild-type. T3 administration restored TRbeta, RC3 and CaMKII levels in hypothyroid wild-type mice, without significant Rhes upregulation. T3 administration normalised expression of all genes studied in hypothyroid TRbeta(-/-) but not TRalpha(0/0) mice. Thus, TRalpha apparently plays an essential role in restoring the expression of the TH-regulated genes potentially involved in striatal synaptic plasticity.
Subject(s)
Corpus Striatum/physiology , Gene Expression Regulation , Hypothyroidism/metabolism , Neuronal Plasticity/genetics , Thyroid Hormone Receptors alpha/metabolism , Animals , Humans , Hypothyroidism/genetics , Mice , Mice, Knockout , Thyroid Hormone Receptors alpha/genetics , Thyroid Hormone Receptors beta/genetics , Thyroid Hormone Receptors beta/metabolism , Thyroid Hormones/genetics , Thyroid Hormones/metabolismABSTRACT
The aim of the present work was to assess whether changes in adipose tissue geneexpression related with adipogenesis and/or thermogenesis could be involved in themechanism conferring susceptibility or resistance to develop obesity in high-fat fedoutbreed rats. For this purpose, male Wistar rats were fed with standard laboratorydiet (control group) or high fat diet. After 15 days, two groups of rats with significantdifferences on body weight gain in response to the high fat diet were characterizedand identified as diet-induced obesity (DIO) and diet resistant (DR) rats. A significantincrease in visceral white adipose tissue (WAT) PPARã and aP2 (p<0.05)mRNA levels associated to a decrease in RARã expression (p<0.05) was observed inDIO rats, suggesting an increase of adipogenesis. Furthermore, our data showed amarked increase in brown adipose tissue (BAT) of UCP1 mRNA in DIO animals(p<0.01) (without affecting PGC-1á gene expression), whereas no changes werefound in WAT UCP2 gene expression. All these data suggest that the variationsfound in the expression pattern of PPARã, aP2 and RARã by high-fat diet could beinvolved, at least in part, in the differences in body weight gain and adiposityobserved between DR and DIO animals. The compensatory adaptations through theincrease in energy expenditure by changes on the expression levels of UCP1 seem notto be enough to avoid the obesity onset in the DIO group (AU)
No disponible
Subject(s)
Animals , Rats , Adipogenesis/genetics , Adipose Tissue/metabolism , Dietary Fats/administration & dosage , Obesity/genetics , Thermogenesis/genetics , Transcription Factors/genetics , RNA-Binding Proteins/genetics , Genetic Predisposition to Disease/genetics , Ion Channels/genetics , Mitochondrial Proteins/genetics , Body Weight/geneticsABSTRACT
The aim of the present work was to assess whether changes in adipose tissue geneexpression related with adipogenesis and/or thermogenesis could be involved in themechanism conferring susceptibility or resistance to develop obesity in high-fat fedoutbreed rats. For this purpose, male Wistar rats were fed with standard laboratorydiet (control group) or high fat diet. After 15 days, two groups of rats with significantdifferences on body weight gain in response to the high fat diet were characterizedand identified as diet-induced obesity (DIO) and diet resistant (DR) rats. A significantincrease in visceral white adipose tissue (WAT) PPARã and aP2 (p<0.05)mRNA levels associated to a decrease in RARã expression (p<0.05) was observed inDIO rats, suggesting an increase of adipogenesis. Furthermore, our data showed amarked increase in brown adipose tissue (BAT) of UCP1 mRNA in DIO animals(p<0.01) (without affecting PGC-1á gene expression), whereas no changes werefound in WAT UCP2 gene expression. All these data suggest that the variationsfound in the expression pattern of PPARã, aP2 and RARã by high-fat diet could beinvolved, at least in part, in the differences in body weight gain and adiposityobserved between DR and DIO animals. The compensatory adaptations through theincrease in energy expenditure by changes on the expression levels of UCP1 seem notto be enough to avoid the obesity onset in the DIO group (AU)
No disponible
Subject(s)
Animals , Rats , Male , Obesity/physiopathology , Obesity/veterinary , Dietary Fats/metabolism , Dietary Fats/therapeutic use , Body Weight/physiology , Thermogenesis/physiology , Interleukin-11/physiology , Adipose Tissue/physiology , Body Weight , Thermogenesis , Thermogenesis/immunologyABSTRACT
The aim of the present work was to assess whether changes in adipose tissue gene expression related with adipogenesis and/or thermogenesis could be involved in the mechanism conferring susceptibility or resistance to develop obesity in high-fat fed outbreed rats. For this purpose, male Wistar rats were fed with standard laboratory diet (control group) or high fat diet. After 15 days, two groups of rats with significant differences on body weight gain in response to the high fat diet were characterized and identified as diet-induced obesity (DIO) and diet resistant (DR) rats. A significant increase in visceral white adipose tissue (WAT) PPARgamma and aP2 (p < 0.05) mRNA levels associated to a decrease in RARgamma expression (p < 0.05) was observed in DIO rats, suggesting an increase of adipogenesis. Furthermore, our data showed a marked increase in brown adipose tissue (BAT) of UCP1 mRNA in DIO animals (p < 0.01) (without affecting PGC-1alpha gene expression), whereas no changes were found in WAT UCP2 gene expression. All these data suggest that the variations found in the expression pattern of PPARgamma, aP2 and RARgamma by high-fat diet could be involved, at least in part, in the differences in body weight gain and adiposity observed between DR and DIO animals. The compensatory adaptations through the increase in energy expenditure by changes on the expression levels of UCP1 seem not to be enough to avoid the obesity onset in the DIO group.
Subject(s)
Adipogenesis/genetics , Adipose Tissue/metabolism , Dietary Fats/administration & dosage , Obesity/genetics , Thermogenesis/genetics , Animals , Body Weight/genetics , Genetic Predisposition to Disease/genetics , Ion Channels/genetics , Male , Mitochondrial Proteins/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , RNA-Binding Proteins/genetics , Rats , Rats, Wistar , Transcription Factors/genetics , Uncoupling Protein 1 , Uncoupling Protein 2ABSTRACT
The aim of this study was to determine the effects of cafeteria diet containing control or elevated level of vitamin A on the expression of nuclear receptors in adipose tissue. Male Wistar rats were submitted to 3 experimental diets during 8 weeks, a standard diet and two hyper-energetic, hyperlipidic "cafeteria" diets containing normal (Caf) or higher (Caf+) vitamin A level. During the experiment, body weights and energy intakes were measured. At the end of the experimental period, subcutaneous adipose tissue (Swat) and all the fat mass were removed and weighted. Nuclear receptors mRNA levels of RARalpha, RARgamma, RXRalpha, PPARgamma were measured in the Swat by a real-time semi-quantitative RT-PCR method. We observed that energy intake of Caf+ and Caf groups was significantly higher than that of the control group. Despite a higher increase of the energy intake in the Caf group compared to the Caf+ group, no significant difference was observed in the body weight gain of the Caf+ compared to the Caf group. The Caf+ and Caf diets led to a significant increase of adipose tissue in cafeteria groups as observed in the Swat depot. The mRNA levels of PPARgamma and RXRalpha were significantly increased in the Caf+ group as compared to control group, with a significant positive correlation between these two parameters. Expressions of RARalpha and RARgamma were not modified in experimental groups compared to controls. In conclusion, 8-week exposure to cafeteria diets with normal and higher levels of vitamin A led to an increase of adiposity in rats, associated, only in the group fed with the higher vitamin A level cafeteria diet, with an increase of PPARgamma and RXRalpha expressions in subcutaneous adipose tissue.
Subject(s)
Adipose Tissue/metabolism , Diet , Gene Expression Regulation/physiology , Receptors, Cytoplasmic and Nuclear/metabolism , Vitamin A/metabolism , Animals , Energy Intake , Male , PPAR gamma/genetics , PPAR gamma/metabolism , Polymerase Chain Reaction , RNA, Messenger/analysis , Rats , Rats, Wistar , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Retinoic Acid/genetics , Receptors, Retinoic Acid/metabolism , Retinoic Acid Receptor alpha , Retinoid X Receptor alpha/genetics , Retinoid X Receptor alpha/metabolism , Time Factors , Retinoic Acid Receptor gammaABSTRACT
In vivo assessment of the cellular impact of thyroid hormones on target tissues might be of help for physiological studies and to evaluate the consequences of various diseases of the thyroid gland in humans. Given the tenuous relationship between retinoid and tri-iodothyronine (T3) status and that retinoids have also intracellular roles, the aim of this study was to determine the effect of hypothyroidism on the expression of T3 nuclear receptors (TR) and retinoic acid nuclear receptors (RAR, RXR) in human peripheral blood mononuclear cells (PBMC). Using real time RT-PCR, we quantified the relative amount of mRNA of the thyroid (TR alpha and TR beta) and retinoid (RAR alpha, RAR gamma, and RXR alpha) nuclear receptors in PBMC of euthyroid (n = 22) compared with hypothyroid (n = 22) subjects. Classical plasma parameters (free T3 (FT3), free thyroxine (T4) (FT4), thyroid-stimulating hormone (TSH), retinol (ROH), retinol-binding protein (RBP) and transthyretin (TTR)) were also measured. In hypothyroid subjects, the concentration of TSH was elevated, and dramatically low T3 and T4 concentrations were associated with a decrease in the expression of TR beta. Expression of RAR alpha and RAR gamma significantly decreased in hypothyroid versus control subjects, while an increased concentration of ROH was emphasised by hypothyroidism. These results first indicated that primary hypothyroidism induces hypoactivation of the retinoid nuclear pathway in PBMC, which was not predicted by the plasma ROH level. Further investigations will be necessary to evaluate these parameters in very small changes in thyroid hormone production such as mild (subclinical) hypothyroidism.