scholarly journals Effects of Exercise, Metformin, Pioglitazone and Exenatide Treatment on Inflammation Induced Insulin Resistance and Ubiquitin Proteasome System in Diabetes and Obesity

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A438-A438
Author(s):  
Ersin Akarsu ◽  
Can Demirel ◽  
Sibel Oguzkan Balci ◽  
Zeynel A Sayiner ◽  
İbrahim Yilmaz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Liver Tissue ◽  
Molecular Mechanisms ◽  
Immunohistochemical Analysis ◽  
Ubiquitin Proteasome System ◽  
Diabetic Animal ◽  
Ubiquitin Proteasome ◽  
Treatment Of Diabetes ◽  
Diabetes And Obesity

Abstract Purpose: The aim of this study is; To examine the destruction of insulin receptor substrate-1 (IRS-1) molecule, which is one of the mechanisms that cause insulin resistance in diabetes and obesity, and its effect to reduce this destruction. For this purpose, the effects of exercise, metformin, exenatide and pioglitazone treatments on IRS-1 ubiquitination in pancreas, muscle and adipose tissue were investigated in an obese and diabetic animal model. Method: Obese rat model was used in this study. This model is characterised by obesity, diabetes and insulin resistance. This study investigated the molecular mechanisms of IRS-1 breakdown in diabetes. IRS1, SOCS1, SOC3 expressions were evaluated in the liver, muscle and adipose tissue of this model. At the same time, immunohistochemical analyses were performed in terms of IRS1, SOCS1 and SOCS3 in the same tissues. Results: Gene expression and Immunohistochemical analysis results were evaluated, the increase in IRS1 was noticeable in rats treated with exenatide, especially in the liver tissue despite the greater decrease in SOCS1 (P> 0.05). It was determined that other drugs in this study and used in the treatment of diabetes may also affect this mechanism to different degrees. Conclusion: Our findings showed that some drugs used in the treatment of diabetes may alter the SOCS effect and / or proteasomal degradation of the IRS-1 protein. This effect was particularly pronounced in liver tissue. However, more comprehensive studies are required to show the contribution of ubiquitination in the destruction of IRS-1 and which drugs are effective on this mechanism. Acknowledgement: This study was supported by the Scientific And Tecnological Research Council Of Turkey (TÜBİTAK) Project No: 217S089

Inflammation and impaired adipogenesis in hypertrophic obesity in man

2009 ◽  
Vol 297 (5) ◽  
pp. E999-E1003 ◽  
Author(s):  
Birgit Gustafson ◽  
Silvia Gogg ◽  
Shahram Hedjazifar ◽  
Lachmi Jenndahl ◽  
Ann Hammarstedt ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Subcutaneous Adipose Tissue ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Preadipocyte Differentiation ◽  
Metabolic Complications ◽  
Adipose Cell ◽  
Subcutaneous Adipose ◽  
Adipose Cell Size

Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-1 and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP-1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications.

scholarly journals Determinants and correlates of adipose tissue insulin resistance index in Japanese women without diabetes and obesity

2020 ◽  
Vol 8 (1) ◽  
pp. e001686
Author(s):  
Kaori Kitaoka ◽  
Ayaka Tsuboi ◽  
Satomi Minato-Inokawa ◽  
Mari Honda ◽  
Mika Takeuchi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Young Women ◽  
Fat Mass ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Japanese Women ◽  
Apolipoprotein A1 ◽  
Middle Aged ◽  
Diabetes And Obesity

IntroductionDeterminants and correlates of a novel index of adipose tissue insulin resistance (AT-IR) (the product of fasting insulin and free fatty acid concentrations) were investigated in Japanese women without diabetes and obesity.Research design and methodsCross-sectional associations of AT-IR with fat mass and distribution, and IR-related cardiometabolic variables were examined in 210 young and 148 middle-aged women whose average body mass index (BMI) was <23 kg/m2 and waist was <80 cm. Multivariate linear regression analyses were used to identify most important determinants of AT-IR.ResultsYoung and middle-aged women did not differ in AT-IR (3.5±2.7 and 3.2±2.1, respectively). In both young and middle-aged women, AT-IR was positively associated with trunk/leg fat ratio, a sophisticated measure of abdominal fat accumulation, fasting plasma glucose (FPG), fasting triglycerides (FTG), serum alanine aminotransferase and γ-glutamyl-transpeptidase (all p<0.05). Furthermore, in middle-aged but not in young women, AT-IR showed positive associations with BMI, waist, fat mass index, low-density lipoprotein cholesterol, apolipoprotein B and systolic and diastolic blood pressure (BP) (all p<0.05). AT-IR showed no association with hemoglobin A1c, high-density lipoprotein (HDL) cholesterol and apolipoprotein A1 in two groups of women. On multivariate analysis including waist, FPG, FTG, HDL cholesterol and systolic BP as independent variables, FPG, FTG and HDL cholesterol emerged as independent determinants of AT-IR in young women (cumulative R2=0.141) and waist in middle-aged women (cumulative R2=0.056). In a model which included trunk/leg fat ratio instead of waist, trunk/leg fat ratio and systolic BP were determinants of AT-IR in middle-aged women (cumulative R2=0.093). Results did not alter in young women.ConclusionsAT-IR may be a simple and useful surrogate index of adipose tissue insulin resistance even in populations without diabetes and obesity.

scholarly journals Progress in the pathogenesis and genetics of Parkinson's disease

2008 ◽  
Vol 363 (1500) ◽  
pp. 2215-2227 ◽  
Author(s):  
Yoshikuni Mizuno ◽  
Nobutaka Hattori ◽  
Shin-ichiro Kubo ◽  
Shigeto Sato ◽  
Kenya Nishioka ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Disease Process ◽  
Ubiquitin Proteasome System ◽  
Neurodegenerative Process ◽  
Molecular Events ◽  
Ubiquitin Proteasome ◽  
Sporadic Parkinson’S Disease ◽  
Synuclein Proteins

Recent progresses in the pathogenesis of sporadic Parkinson's disease (PD) and genetics of familial PD are reviewed. There are common molecular events between sporadic and familial PD, particularly between sporadic PD and PARK1 -linked PD due to α - synuclein ( SNCA ) mutations. In sporadic form, interaction of genetic predisposition and environmental factors is probably a primary event inducing mitochondrial dysfunction and oxidative damage resulting in oligomer and aggregate formations of α-synuclein. In PARK1 -linked PD, mutant α-synuclein proteins initiate the disease process as they have increased tendency for self-aggregation. As highly phosphorylated aggregated proteins are deposited in nigral neurons in PD, dysfunctions of proteolytic systems, i.e. the ubiquitin–proteasome system and autophagy–lysosomal pathway, seem to be contributing to the final neurodegenerative process. Studies on the molecular mechanisms of nigral neuronal death in familial forms of PD will contribute further on the understanding of the pathogenesis of sporadic PD.

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

2016 ◽  
Vol 311 (3) ◽  
pp. C392-C403 ◽  
Author(s):  
Philippe A. Bilodeau ◽  
Erin S. Coyne ◽  
Simon S. Wing
Keyword(s):  
Signaling Pathways ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Clinical Problem ◽  
Ubiquitin Proteasome System ◽  
Mechanisms Of Action ◽  
Loss Of Function ◽  
Critical Determinant ◽  
Ubiquitin Proteasome

Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3β, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.

scholarly journals Differential Expression of MicroRNAs in Omental Adipose Tissue From Gestational Diabetes Mellitus Subjects Reveals miR-222 as a Regulator of ERα Expression in Estrogen-Induced Insulin Resistance

Endocrinology ◽  
2014 ◽  
Vol 155 (5) ◽  
pp. 1982-1990 ◽  
Author(s):  
Zhonghua Shi ◽  
Chun Zhao ◽  
Xirong Guo ◽  
Hongjuan Ding ◽  
Yugui Cui ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Differential Expression ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Luciferase Assay ◽  
Omental Adipose Tissue

Omental adipose tissue plays a central role in insulin resistance in gestational diabetes mellitus (GDM), and the molecular mechanisms leading to GDM remains vague. Evidence demonstrates that maternal hormones, such as estradiol, contribute to insulin resistance in GDM. In this study we determined the differential expression patterns of microRNAs (miRNAs) in omental adipose tissues from GDM patients and pregnant women with normal glucose tolerance using AFFX miRNA expression chips. MiR-222, 1 of 17 identified differentially expressed miRNAs, was found to be significantly up-regulated in GDM by quantitative real-time PCR (P &lt; .01), and its expression was closely related with serum estradiol level (P &lt; .05). Furthermore, miR-222 expression was significantly increased in 3T3-L1 adipocytes with a high concentration of 17β-estradiol stimulation (P &lt; .01), whereas the expressions of estrogen receptor (ER)-α protein and insulin-sensitive membrane transporter glucose transporter 4 (GLUT4) protein (P &lt; .01) were markedly reduced. In addition, ERα was shown to be a direct target of miR-222 in 3T3-L1 adipocytes by using the luciferase assay. Finally, antisense oligonucleotides of miR-222 transfection was used to silence miR-222 in 3T3-L1 adipocytes. The results showed that the expressions of ERα and GLUT4, the insulin-stimulated translocation of GLUT4 from the cytoplasm to the cell membrane and glucose uptake in mature adipocytes were dramatically increased (P &lt; .01). In conclusion, miR-222 is a potential regulator of ERα expression in estrogen-induced insulin resistance in GDM and might be a candidate biomarker and therapeutic target for GDM.

scholarly journals Up-Regulation of Genes Related to the Ubiquitin-Proteasome System in the Brown Adipose Tissue of 24-h-Fasted Rats

2008 ◽  
Vol 72 (1) ◽  
pp. 139-148 ◽  
Author(s):  
Yuji NAKAI ◽  
Hiroko HASHIDA ◽  
Koji KADOTA ◽  
Michiko MINAMI ◽  
Kentaro SHIMIZU ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Ubiquitin Proteasome System ◽  
Brown Adipose ◽  
Ubiquitin Proteasome ◽  
Fasted Rats

TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes

2013 ◽  
Vol 305 (1) ◽  
pp. E101-E112 ◽  
Author(s):  
Ana Vázquez-Carballo ◽  
Victòria Ceperuelo-Mallafré ◽  
Matilde R. Chacón ◽  
Elsa Maymó-Masip ◽  
Margarita Lorenzo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Visceral Fat ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Metabolic Effects ◽  
Human Adipocytes ◽  
Fat Depots ◽  
Tnf Α

Visceral fat is strongly associated with insulin resistance. Obesity-associated adipose tissue inflammation and inflammatory cytokine production are considered key mediators of insulin signaling inhibition. TWEAK is a relatively new member of the TNF cytokine superfamily, which can exist as full length membrane-associated (mTWEAK) and soluble (sTWEAK) isoforms. Although TWEAK has been shown to have important functions in chronic inflammatory diseases its physiological role in adipose tissue remains unresolved. In this study, we explore the molecular mechanisms involved in the modulation of TNF-α-induced effects on insulin sensitivity by sTWEAK in a human visceral adipose cell line and also in primary human adipocytes obtained from visceral fat depots. Our data reveal that sTWEAK ameliorates TNF-α-induced insulin resistance on glucose uptake, GLUT4 translocation and insulin signaling without affecting other metabolic effects of TNF-α such as lipolysis or apoptotis. Co-immunoprecipitation experiments in adipose cells revealed that pretreatment with sTWEAK specifically inhibits TRAF2 association with TNFR1, but not with TNFR2, which mediates insulin resistance. However, sTWEAK does not affect other downstream molecules activated by TNF-α, such as TAK1. Rather, sTWEAK abolishes the stimulatory effect of TNF-α on JNK1/2, which is directly involved in the development of insulin resistance. This is associated with an increase in PP2A activity upon sTWEAK treatment. Silencing of the PP2A catalytic subunit gene overcomes the dephosphorylation effect of sTWEAK on JNK1/2, pointing to PP2A as a relevant mediator of sTWEAK-induced JNK inactivation. Overall, our data reveal a protective role of TWEAK in glucose homeostasis and identify PP2A as a new driver in the modulation of TNF-α signaling by sTWEAK.

scholarly journals Role of Insulin Receptor Substrate-1 Serine 307 Phosphorylation and Adiponectin in Adipose Tissue Insulin Resistance in Late Pregnancy

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 5933-5942 ◽  
Author(s):  
Julio Sevillano ◽  
Javier de Castro ◽  
Carlos Bocos ◽  
Emilio Herrera ◽  
M. Pilar Ramos
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Late Pregnancy ◽  
Serine Phosphorylation ◽  
Pregnant Rats

Insulin resistance is a hallmark of late pregnancy both in human and rat. Adipose tissue is one of the tissues that most actively contributes to this reduced insulin sensitivity. The aim of the present study was to characterize the molecular mechanisms of insulin resistance in adipose tissue at late pregnancy. To this end, we analyzed the insulin signaling cascade in lumbar adipose tissue of nonpregnant and pregnant (d 20) rats both under basal and insulin-stimulated conditions. We found that the levels of relevant signaling proteins, such as insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3-kinase, 3-phosphoinositide-dependent kinase-1, ERK1/2, and phosphatase and tensin homolog (PTEN) did not change at late pregnancy. However, insulin-stimulated tyrosine phosphorylation of both IR and IRS-1 were significantly decreased, coincident with decreased IRS-1/p85 association and impaired phosphorylation of AKR mouse thymoma viral protooncogene (Akt) and ERK1/2. This impaired activation of IRS-1 occurred together with an increase of IRS-1 phosphorylation at serine 307 and a decrease in adiponectin levels. To corroborate the role of IRS-1 in adipose tissue insulin resistance during pregnancy, we treated pregnant rats with the antidiabetic drug englitazone. Englitazone improved glucose tolerance, and this pharmacological reversal of insulin resistance was paralleled by an increase of adiponectin levels in adipose tissue as well as by a reduction of IRS-1 serine phosphorylation. Furthermore, the impaired insulin-stimulated tyrosine phosphorylation of IRS-1 in adipose tissue of pregnant animals could be restored ex vivo by treating isolated adipocytes with adiponectin. Together, our findings support a role for adiponectin and serine phosphorylation of IRS-1 in the modulation of insulin resistance in adipose tissue at late pregnancy.

scholarly journals Abnormal Ubiquitination of Ubiquitin-Proteasome System in Lung Squamous Cell Carcinomas

2020 ◽  
Author(s):  
Xianquan Zhan ◽  
Miaolong Lu
Keyword(s):  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Lung Squamous Cell Carcinoma ◽  
Ubiquitin Proteasome System ◽  
Quantitative Information ◽  
Scientific Data ◽  
Label Free ◽  
Ubiquitinated Proteins ◽  
The Status ◽  
Ubiquitin Proteasome

Ubiquitination is an important post-translational modification. Abnormal ubiquitination is extensively associated with cancers. Lung squamous cell carcinoma (LUSC) is the most common pathological type of lung cancer, with unclear molecular mechanism and the poor overall prognosis of LUSC patient. To uncover the existence and potential roles of ubiquitination in LUSC, label-free quantitative ubiquitomics was performed in human LUSC vs. control tissues. In total, 627 ubiquitinated proteins (UPs) with 1209 ubiquitination sites were identified, including 1133 (93.7%) sites with quantitative information and 76 (6.3%) sites with qualitative information. KEGG pathway enrichment analysis found that UPs were significantly enriched in ubiquitin-mediated proteolysis pathway (hsa04120) and proteasome complex (hsa03050). Further analysis of 400 differentially ubiquitinated proteins (DUPs) revealed that 11 subunits of the proteasome complex were differentially ubiquitinated. These findings clearly demonstrated that ubiquitination was widely present in the ubiquitin-proteasome pathway in LUSCs. At the same time, abnormal ubiquitination might affect the function of the proteasome to promote tumorigenesis and development. This book chapter discussed the status of protein ubiquitination in the ubiquitin-proteasome system (UPS) in human LUSC tissues, which offered the scientific data to elucidate the specific molecular mechanisms of abnormal ubiquitination during canceration and the development of anti-tumor drugs targeting UPS.

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