Resistance to thyroid hormone, and peroxisome-proliferator-activated receptor γ resistance

2001 ◽  
Vol 29 (2) ◽  
pp. 227-230 ◽  
Author(s):  
V. K. K. Chatterjee
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Thyroid Hormone ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Hormone Binding ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dominant Negative Activity ◽  
Mutant Receptors

Resistance to thyroid hormone (RTH) is usually inherited in a dominant fashion, and is characterized by elevated serum thyroid hormone levels and failure to suppress pituitary secretion of thyroid-stimulating hormone, with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features suggesting predominant pituitary resistance (PRTH). In over 100 families with GRTH or PRTH, we have identified heterozygous mutations in the thyroid hormone receptor β isoform (TRβ), which localize to three regions (amino acids 234–282, 310–353 and 429–461) of the hormone-binding domain of the receptor. The mutant receptors are transcriptionally impaired, due either to reduced ligand binding or to attenuated interaction with co-activators, and inhibit wild-type TR action in a dominant-negative manner. In the TRβ crystal structure, most RTH mutations cluster around the hormone-binding pocket, with receptor regions that mediate functions (DNA binding, dimerization, corepressor recruitment) required for dominant-negative activity being devoid of natural mutations. The pathogenesis of variable tissue resistance is not fully understood, but may be related to the differing tissue distributions of TRα and TRβ, and to variable dominant-negative activity of mutant receptors on different target genes. The nuclear receptor peroxisome-proliferator-activated receptor γ (PPARγ) regulates adipogenesis and mediates the action of thiazolidinediones - novel antidiabetic agents which enhance tissue insulin sensitivity. The PPARγ gene was screened in 85 subjects with severe insulin resistance, and two different heterozygous receptor mutations (P467L and V290M) were identified in three affected individuals. The PPARγ mutants are markedly transcriptionally impaired due to altered ligand binding and co-activator recruitment. Analogous to RTH, they inhibit the function of wild-type PPARγ when co-expressed, and such dominant-negative inhibition is linked to their ability to silence basal gene transcription via aberrant interaction with co-repressors. In addition to insulin resistance, all three affected subjects developed Type II diabetes mellitus and hypertension at an unusually early age. Our findings provide compelling evidence that PPARγ is important in the control of insulin sensitivity, glucose homoeostasis and blood pressure in humans. Future studies aim to elucidate the mechanism by which this receptor regulates insulin action and vascular tone.

scholarly journals The role of the amino-terminal domain in the interaction of unliganded peroxisome proliferator-activated receptor γ-2 with nuclear receptor co-repressor

2010 ◽  
Vol 45 (3) ◽  
pp. 133-145 ◽  
Author(s):  
Sadako Suzuki ◽  
Shigekazu Sasaki ◽  
Hiroshi Morita ◽  
Yutaka Oki ◽  
Daisuke Turiya ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Nuclear Receptor ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Amino Terminal

Peroxisome proliferator-activated receptor γ-2 (PPARG2) is a ligand-dependent transcriptional factor involved in the pathogenesis of insulin resistance. In the presence of a ligand, PPARG2 associates with co-activators, while it recruits co-repressors (CoRs) in the absence of a ligand. It has been reported that the interaction of liganded PPARG2 with co-activators is regulated by the amino-terminal A/B domain (NTD) via inter-domain communication. However, the role of the NTD is unknown in the case of the interaction between unliganded PPARG2 and CoRs. To elucidate this, total elimination of the influence of ligands is required, but the endogenous ligands of PPARG2 have not been fully defined. PPARG1-P467L, a naturally occurring mutant of PPARG1, was identified in a patient with severe insulin resistance. Reflecting its very low affinity for various ligands, this mutant does not have transcriptional activity in the PPAR response element, but exhibits dominant negative effects (DNEs) on liganded wild-type PPARG2-mediated transactivation. Using the corresponding PPARG2 mutant, PPARG2-P495L, we evaluated the role of the NTD in the interaction between unliganded PPARG2 and CoRs. Interestingly, the DNE of PPARG2-P495L was increased by the truncation of its NTD. NTD deletion also enhanced the DNE of a chimeric receptor, PT, in which the ligand-binding domain of PPARG2 was replaced with that of thyroid hormone receptor β-1. Moreover, NTD deletion facilitated the in vitro binding of nuclear receptor CoR with wild-type PPARG2, mutant P495L, and the PT chimera (PPARG2-THRB). Inter-domain communication in PPARG2 regulates not only ligand-dependent transactivation but also ligand-independent silencing.

scholarly journals Skeletal muscle mitochondrial and metabolic responses to a high-fat diet in female rats bred for high and low aerobic capacity

2010 ◽  
Vol 35 (2) ◽  
pp. 151-162 ◽  
Author(s):  
Scott P. Naples ◽  
Sarah J. Borengasser ◽  
R. Scott. Rector ◽  
Grace M. Uptergrove ◽  
E. Matthew Morris ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Female Rats ◽  
Mitochondrial Morphology ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Transcriptional Responses ◽  
Peroxisome Proliferator Activated Receptor

Rats selected artificially to be low-capacity runners (LCR) possess a metabolic syndrome phenotype that is worsened by a high-fat diet (HFD), whereas rats selected to be high-capacity runners (HCR) are protected against HFD-induced obesity and insulin resistance. This study examined whether protection against, or susceptibility to, HFD-induced insulin resistance in the HCR–LCR strains is associated with contrasting metabolic adaptations in skeletal muscle. HCR and LCR rats (generation 20; n = 5–6; maximum running distance ∼1800 m vs. ∼350 m, respectively (p < 0.0001)) were divided into HFD (71.6% energy from fat) or normal chow (NC) (16.7% energy from fat) groups for 7 weeks (from 24 to 31 weeks of age). Skeletal muscle (red gastrocnemius) mitochondrial-fatty acid oxidation (FAO), mitochondrial-enzyme activity, mitochondrial-morphology, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and peroxisome proliferator-activated receptor δ (PPARδ) expression and insulin sensitivity (intraperitoneal glucose tolerance tests) were measured. The HFD caused increased adiposity and reduced insulin sensitivity only in the LCR and not the HCR strain. Isolated mitochondria from the HCR skeletal muscle displayed a 2-fold-higher rate of FAO on NC, but both groups increased FAO following HFD. PGC-1α mRNA expression and superoxide dismutase activity were significantly reduced with the HFD in the LCR rats, but not in the HCR rats. PPARδ expression did not differ between strains or dietary conditions. These results do not provide a clear connection between protection of insulin sensitivity and HFD-induced adaptive changes in mitochondrial function or transcriptional responses but do not dismiss the possibility that elevated mitochondrial FAO in the HCR may play a protective role.

scholarly journals Impaired Peroxisome Proliferator-Activated Receptor γ Function through Mutation of a Conserved Salt Bridge (R425C) in Familial Partial Lipodystrophy

2007 ◽  
Vol 21 (5) ◽  
pp. 1049-1065 ◽  
Author(s):  
Ellen H. Jeninga ◽  
Olivier van Beekum ◽  
Aalt D. J. van Dijk ◽  
Nicole Hamers ◽  
Brenda I. Hendriks-Stegeman ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Transcriptional Activity ◽  
Salt Bridge ◽  
Dominant Negative ◽  
Heterozygous Mutation ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Partial Lipodystrophy ◽  
Familial Partial Lipodystrophy

Abstract The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ plays a key role in the regulation of glucose and lipid metabolism in adipocytes by regulating their differentiation, maintenance, and function. A heterozygous mutation in the PPARG gene, which changes an arginine residue at position 425 into a cysteine (R425C), has been reported in a patient with familial partial lipodystrophy subtype 3 (FPLD3). The strong conservation of arginine 425 among nuclear receptors that heterodimerize with retinoic acid X receptor prompted us to investigate the functional consequences of the R425C mutation on PPARγ function. Here we show that this mutant displayed strongly reduced transcriptional activity compared with wild-type PPARγ, irrespective of cell type, promoter context, or ligand, whereas transrepression of nuclear factor-κB activity remained largely intact. Our data indicate that the reduced transcriptional activity of PPARγ R425C is not caused by impaired corepressor release, but due to reduced dimerization with retinoic acid X receptor α in combination with reduced ligand binding and subsequent coactivator binding. As a consequence of these molecular defects, the R425C mutant was less effective in inducing adipocyte differentiation. PPARγ R425C did not inhibit its wild-type counterpart in a dominant-negative manner, suggesting a haploinsufficiency mechanism in at least some FPLD3 patients. Using molecular dynamics simulations, substitution of R425 with cysteine is predicted to cause the formation of an alternative salt bridge. This structural change provides a likely explanation of how mutation of a single conserved residue in a patient with FPLD3 can disrupt the function of the adipogenic transcription factor PPARγ on multiple levels.

scholarly journals Classic and Novel Sex Hormone Binding Globulin Effects on the Cardiovascular System in Men

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Carla Basualto-Alarcón ◽  
Paola Llanos ◽  
Gerardo García-Rivas ◽  
Mayarling Francisca Troncoso ◽  
Daniel Lagos ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Sex Hormone ◽  
Membrane Receptors ◽  
Sex Hormone Binding Globulin ◽  
Target Cells ◽  
Peroxisome Proliferator ◽  
Hormone Binding ◽  
Peroxisome Proliferator Activated Receptor ◽  
Plasma Membrane Receptors ◽  
Local Expression

In men, 70% of circulating testosterone binds with high affinity to plasma sex hormone binding globulin (SHBG), which determines its bioavailability in their target cells. In recent years, a growing body of evidence has shown that circulating SHBG not only is a passive carrier for steroid hormones but also actively regulates testosterone signaling through putative plasma membrane receptors and by local expression of androgen-binding proteins apparently to reach local elevated testosterone concentrations in specific androgen target tissues. Circulating SHBG levels are influenced by metabolic and hormonal factors, and they are reduced in obesity and insulin resistance, suggesting that SHBG may have a broader clinical utility in assessing the risk for cardiovascular diseases. Importantly, plasma SHBG levels are strongly correlated with testosterone concentrations, and in men, low testosterone levels are associated with an adverse cardiometabolic profile. Although obesity and insulin resistance are associated with an increased incidence of cardiovascular disease, whether they lead to abnormal expression of circulating SHBG or its interaction with androgen signaling remains to be elucidated. SHBG is produced mainly in the liver, but it can also be expressed in several tissues including the brain, fat tissue, and myocardium. Expression of SHBG is controlled by peroxisome proliferator-activated receptor γ (PPARγ) and AMP-activated protein kinase (AMPK). AMPK/PPAR interaction is critical to regulate hepatocyte nuclear factor-4 (HNF4), a prerequisite for SHBG upregulation. In cardiomyocytes, testosterone activates AMPK and PPARs. Therefore, the description of local expression of cardiac SHBG and its circulating levels may shed new light to explain physiological and adverse cardiometabolic roles of androgens in different tissues. According to emerging clinical evidence, here, we will discuss the potential mechanisms with cardioprotective effects and SHBG levels to be used as an early metabolic and cardiovascular biomarker in men.

scholarly journals Low-Frequency Electroacupuncture Improves Insulin Sensitivity in Obese Diabetic Mice through Activation of SIRT1/PGC-1αin Skeletal Muscle

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Fengxia Liang ◽  
Rui Chen ◽  
Atsushi Nakagawa ◽  
Makoto Nishizawa ◽  
Shinichi Tsuda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Fasting Blood Glucose ◽  
Low Frequency ◽  
Tolerance Test ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Obesity And Diabetes

Electroacupuncture (EA) has been observed to reduce insulin resistance in obesity and diabetes. However, the biochemical mechanism underlying this effect remains unclear. This study investigated the effects of low-frequency EA on metabolic action in genetically obese and type 2 diabetic db/db mice. Nine-week-old db/m and db/db mice were randomly divided into four groups, namely, db/m, db/m + EA, db/db, and db/db + EA. db/m + EA and db/db + EA mice received 3-Hz electroacupuncture five times weekly for eight consecutive weeks. In db/db mice, EA tempered the increase in fasting blood glucose, food intake, and body mass and maintained insulin levels. In EA-treated db/db mice, improved insulin sensitivity was established through intraperitoneal insulin tolerance test. EA was likewise observed to decrease free fatty acid levels in db/db mice; it increased protein expression in skeletal muscle Sirtuin 1 (SIRT1) and induced gene expression of peroxisome proliferator-activated receptor coactivator (PGC-), nuclear respiratory factor 1 (NRF1), and acyl-CoA oxidase (ACOX). These results indicated that EA offers a beneficial effect on insulin resistance in obese and diabetic db/db mice, at least partly, via stimulation of SIRT1/PGC-, thus resulting in improved insulin signal.

scholarly journals A Novel Peroxisome Proliferator-activated Receptor γ Isoform with Dominant Negative Activity Generated by Alternative Splicing

2005 ◽  
Vol 280 (28) ◽  
pp. 26517-26525 ◽  
Author(s):  
Lina Sabatino ◽  
Amelia Casamassimi ◽  
Gianfranco Peluso ◽  
Maria Vittoria Barone ◽  
Daniela Capaccio ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dominant Negative Activity

scholarly journals The effects of obesity-associated insulin resistance on mRNA expression of peroxisome proliferator-activated receptor-γ target genes, in dogs

2007 ◽  
Vol 98 (3) ◽  
pp. 497-503 ◽  
Author(s):  
Constance Gayet ◽  
Veronique Leray ◽  
Masayuki Saito ◽  
Brigitte Siliart ◽  
Patrick Nguyen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism ◽  
Visceral Adipose

Visceral adipose tissue and skeletal muscle have central roles in determining whole-body insulin sensitivity. The peroxisome proliferator-activated receptor-γ (PPARγ) is a potential mediator of insulin sensitivity. It can directly modulate the expression of genes that are involved in glucose and lipid metabolism, including GLUT4, lipoprotein lipase (LPL) and adipocytokines (leptin and adiponectin). In this study, we aimed to determine the effects of obesity-associated insulin resistance on mRNA expression of PPARγ and its target genes. Dogs were studied when they were lean and at the end of an overfeeding period when they had reached a steady obese state. The use of a sensitive, real-time PCR assay allowed a relative quantification of mRNA expression for PPARγ, LPL, GLUT4, leptin and adiponectin, in adipose tissue and skeletal muscle. In visceral adipose tissue and/or skeletal muscle, mRNA expression of PPARγ, LPL and GLUT4 were at least 2-fold less in obese and insulin-resistant dogs compared with the same animals when they were lean and insulin-sensitive. The mRNA expression and plasma concentration of leptin was increased, whereas the plasma level and mRNA expression of adiponectin was decreased, by obesity. In adipose tissue, PPARγ expression was correlated with leptin and adiponectin. These findings, in an original model of obesity induced by a prolonged period of overfeeding, showed that insulin resistance is associated with a decrease in PPARγ mRNA expression that could dysregulate expression of several genes involved in glucose and lipid metabolism.

scholarly journals Adipogenesis is differentially impaired by thyroid hormone receptor mutant isoforms

2010 ◽  
Vol 44 (4) ◽  
pp. 247-255 ◽  
Author(s):  
Alok Mishra ◽  
Xu-guang Zhu ◽  
Kai Ge ◽  
Sheue-Yann Cheng
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Fold Increase ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Loss Of Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels

To understand the roles of thyroid hormone receptors (TRs) in adipogenesis, we adopted a loss-of-function approach. We generated 3T3-L1 cells stably expressing either TRα1 mutant (TRα1PV) or TRβ1 mutant (TRβ1PV). TRα1PV and TRβ1PV are dominant negative mutations with a frameshift in the C-terminal amino acids. In control cells, the thyroid hormone, tri-iodothyronine (T3), induced a 2.5-fold increase in adipogenesis in 3T3-L1 cells, as demonstrated by increased lipid droplets. This increase was mediated by T3-induced expression of the peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), which are master regulators of adipogenesis at both the mRNA and protein levels. In 3T3-L1 cells stably expressing TRα1PV (L1-α1PV cells) or TRβ1PV (L1-β1PV cells), adipogenesis was reduced 94 or 54% respectively, indicative of differential inhibitory activity of mutant TR isoforms. Concordantly, the expression of PPARγ and C/EBPα at the mRNA and protein levels was more repressed in L1-α1PV cells than in L1-β1PV cells. In addition, the expression of PPARγ downstream target genes involved in fatty acid synthesis – the lipoprotein lipase (Lpl) and aP2 involved in adipogenesis – was more inhibited by TRα1PV than by TRβ1PV. Chromatin immunoprecipitation assays showed that TRα1PV was more avidly recruited than TRβ1PV to the promoter to preferentially block the expression of the C/ebpα gene. Taken together, these data indicate that impaired adipogenesis by mutant TR is isoform dependent. The finding that induction of adipogenesis is differentially regulated by TR isoforms suggests that TR isoform-specific ligands could be designed for therapeutic intervention for lipid abnormalities.

Electroacupuncture combined with acarbose improves insulin sensitivity via peroxisome proliferator–activated receptor γ activation and produces a stronger glucose-lowering effect than acarbose alone in a rat model of steroid-induced insulin resistance

2020 ◽  
Vol 38 (5) ◽  
pp. 335-342
Author(s):  
Yuan-Chiang Chung ◽  
Ying-I Chen ◽  
Chih-Ming Lin ◽  
Su-Wei Chang ◽  
Tai-Hao Hsu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Wistar Rats ◽  
Combined Therapy ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Lowering ◽  
Lowering Effect ◽  
Plasma Ffa ◽  
Glucose Lowering Effect

Background: Previous studies have reported that electroacupuncture (EA) induces a glucose-lowering effect by improving insulin resistance (IR) and reduces plasma free fatty acid (FFA) levels in rats with steroid-induced insulin resistance (SIIR). In addition, EA can activate cholinergic nerves and stimulate endogenous opioid peptides to lower plasma glucose in streptozotocin-induced hyperglycemic rats. The aim of this study was to investigate the glucose-lowering effects of 15 Hz EA at bilateral ST36 in combination with acarbose (ACA). We hypothesized that EA combined with ACA would produce a stronger glucose-lowering effect than ACA alone. Methods: In this study, normal Wistar rats and SIIR rats were randomly divided into two groups: ACA and ACA + EA. To explore the potential mechanisms underlying the glucose-lowering effect, plasma FFA/insulin and insulin transduction signal pathway proteins were assayed. Results: Combined ACA + EA treatment had a greater glucose-lowering effect than ACA alone in normal Wistar rats (−45% ± 3% vs −19% ± 3%, p < 0.001) and SIIR model rats (−43% ± 2% vs −16% ± 6%, p < 0.001). A significant reduction in plasma FFA levels, improvement in homeostatic model assessment of IR (HOMA-IR) index (−48.9% ± 4.0%, p < 0.001) and insulin sensitivity index (102% ± 16.9%, p < 0.001), and significant increases in insulin receptor substrate 1, glucose transporter 4, and peroxisome proliferator–activated receptor γ protein expressions in skeletal muscle, were also observed in the ACA + EA group of SIIR rats. Conclusion: Combined EA and ACA therapy had a greater glucose-lowering effect than ACA monotherapy; this combined therapy could be more effective at improving IR in SIIR rats, which may be related to a reduction in plasma FFA levels and an elevation of insulin signaling proteins. Whether this combined therapy has an effect in type 2 diabetes mellitus (T2DM) patients still needs to be explored.

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