scholarly journals A PIP3phosphatase SKIP links endoplasmic reticulum stress in skeletal muscle to insulin resistance

2015 ◽  
pp. MCB.00921-15 ◽  
Author(s):  
Takeshi Ijuin ◽  
Tetsuya Hosooka ◽  
Tadaomi Takenawa
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Glucose Disposal ◽  
Inositol Polyphosphate ◽  
Insulin Dependent ◽  
Activating Transcription Factor

Insulin resistance is critical in the pathogenesis of type 2 diabetes. Endoplasmic reticulum (ER) stress in liver and adipose tissues plays an important role in the development of insulin resistance. Although skeletal muscle is a primary site for insulin dependent-glucose disposal, it is unclear if ER stress in those tissue contributes to insulin resistance. In this study, we show that skeletal muscle and kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP3phosphatase, links ER stress to insulin resistance in skeletal muscle. SKIP expression was increased due to ER stress, and was higher in the skeletal muscle isolated from high fat diet-fed mice anddb/dbmice than that from wild-type mice. Mechanistically, ER stress promotes activating transcription factor 6 (ATF6) and X-box binding protein 1 (XBP1)-dependent expression of SKIP. These findings underscore the specific and prominent role of SKIP in the development of insulin resistance in skeletal muscle.

scholarly journals Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance

2020 ◽  
Vol 21 (17) ◽  
pp. 6358 ◽  
Author(s):  
Benjamin Lair ◽  
Claire Laurens ◽  
Bram Van Den Bosch ◽  
Cedric Moro
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Acyl Chain ◽  
The Body ◽  
Glucose Disposal ◽  
Tissue Lipid ◽  
Lipid Species ◽  
Chain Composition

A large number of studies reported an association between elevated circulating and tissue lipid content and metabolic disorders in obesity, type 2 diabetes (T2D) and aging. This state of uncontrolled tissue lipid accumulation has been called lipotoxicity. It was later shown that excess lipid flux is mainly neutralized within lipid droplets as triglycerides, while several bioactive lipid species such as diacylglycerols (DAGs), ceramides and their derivatives have been mechanistically linked to the pathogenesis of insulin resistance (IR) by antagonizing insulin signaling and action in metabolic organs such as the liver and skeletal muscle. Skeletal muscle and the liver are the main sites of glucose disposal in the body and IR in these tissues plays a pivotal role in the development of T2D. In this review, we critically examine recent literature supporting a causal role of DAGs and ceramides in the development of IR. A particular emphasis is placed on transgenic mouse models with modulation of total DAG and ceramide pools, as well as on modulation of specific subspecies, in relation to insulin sensitivity. Collectively, although a wide number of studies converge towards the conclusion that both DAGs and ceramides cause IR in metabolic organs, there are still some uncertainties on their mechanisms of action. Recent studies reveal that subcellular localization and acyl chain composition are determinants in the biological activity of these lipotoxic lipids and should be further examined.

scholarly journals The Role of Skeletal Muscle Tribbles 3 (TRB3) on Endoplasmic Reticulum (ER) stress‐ and high fat diet‐induced insulin resistance

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Ho‐Jin Koh ◽  
Taro Toyoda ◽  
Michelle M Jung ◽  
Min‐Young Lee ◽  
Michael F Hirshman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
High Fat Diet ◽  
High Fat

Abstract 357: Hepatic ERK2 Suppresses Endoplasmic Reticulum Stress, Leading to Protection from Oxidative Stress and Endothelial Dysfunction

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Takehiko Kujiraoka ◽  
Yasushi Satoh ◽  
Makoto Ayaori ◽  
Yasunaga Shiraishi ◽  
Yuko Arai-Nakaya ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Fatty Acid ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Vascular Complications ◽  
Metabolic Remodeling ◽  
And Oxidative Stress

Background Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction. Methods Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta. Results The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them. Conclusions Hepatic ERK2 revealed the suppression of hepatic ER stress and HST in vivo , which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.

Fenofibrate Ameliorates Insulin Resistance of Lipoprotein Lipase Knockout Heterozygous Mice

2020 ◽  
Author(s):  
Yangxue Li ◽  
Tingting Han ◽  
Shuang Zheng ◽  
Xingxing Ren ◽  
Yaomin Hu
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Glucose Tolerance ◽  
Er Stress ◽  
Lipid Profile ◽  
Lipoprotein Lipase ◽  
Peroxisome Proliferator ◽  
Phosphorylated Akt

Abstract Background The benefits of fenofibrate (FB), a peroxisome proliferator-activated receptor-a agonist, against hyperlipidemia have been established. We investigated the effect of fenofibrate on insulin resistance of lipoprotein lipase knockout heterozygous (LPL+/-) mice, which represent inherited hypertriglyceridemia and impaired glucose tolerance. Methods Male LPL+/- mice were treated with FB (50 mg/kg, once daily) via gavage for 8 weeks. Plasma lipid, glucose tolerance test, systemic insulin sensitivity, insulin signaling of tissues, genes and proteins related to endoplasmic reticulum (ER) stress and oxidative stress were analyzed. Results Body weight of 40-week LPL+/- with FB were reduced by 30.3% (P<0.05), while the differences of 16- and 28-week LPL+/- with FB were not significant (P>0.05). FB improved the lipid profile of both 28 and 40-week LPL+/- (P<0.001 for both), while that of 16-week LPL+/- mice with FB was unaltered (P>0.05). Glucose tolerance of 40-week LPL+/- were improved by FB (P<0.05), while that of 16- and 28-week LPL+/- with FB kept unaltered (P>0.05). Fasting insulin of 40-week LPL +/- were improved by FB (P<0.05), thus HOMA-IR of 40-week LPL+/- was declined (P<0.05). HOMA-IR of 16- and 28-week LPL+/- with FB had no change. Insulin-stimulated phosphorylated Akt (Ser473) in liver and skeletal muscle of 28-week LPL+/- was enhanced by FB (P < 0.001 and P<0.05 respectively). ER stress biomarkers were detected decreased in liver of 16- to 40-week LPL+/- with FB whereas that in muscle of LPL+/- with FB unchanged. Reduced reactive oxygen species (ROS) levels and augmented mRNA expression of superoxide dismutase (SOD) and catalase (CAT) in skeletal muscle of 28- and 40-week LPL+/- mice with FB were observed. There was no significance on ROS levels and mRNA of SOD and CAT in liver between LPL+/- mice with and without FB. Conclusions Fenofibrate improved lipid profile, glucose tolerance, systemic and tissue-specific insulin resistance of LPL knockout heterozygous mice. This may be associated with alleviated endoplasmic reticulum stress in liver and reduced oxidative stress in muscle.

Role of O-GlcNAcylation and endoplasmic reticulum stress on obesity and insulin resistance

2019 ◽  
Vol 44 (5) ◽  
pp. 599-610 ◽  
Author(s):  
Benan Pelin Sermikli ◽  
Gulizar Aydogdu ◽  
Afsar Abbasi Taghidizaj ◽  
Erkan Yilmaz
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Western Blot ◽  
Er Stress ◽  
Insulin Receptor ◽  
Serine Phosphorylation ◽  
Wild Type ◽  
Adipose Tissues ◽  
Insulin Resistant

Abstract Background Obesity is a global public health problem. Obesity closely associated with various metabolic diseases such as; insulin resistance, hypertension, dyslipidemia and cardiovascular diseases. Endoplasmic reticulum (ER) stress is a critical factor for insulin resistance. O-linked N-acetyl-glucosamine (O-GlcNAc); is the post-translational modification which is has a vital role in biological processes; including cell signaling, in response to nutrients, stress and other extracellular stimuli. Materials and methods In this study, we aimed to investigate the role of O-GlcNAc modification in the context of obesity and obesity-associated insulin resistance in adipose tissue. For this purpose, first, the visceral and epididymal adipose tissues of obese and insulin resistant C57BL/6 Lepob/Lepob and wild-type mice were used to determine the O-GlcNAc modification pattern by western blot. Secondly, the external stimulation of O-GlcNAc modification in wild-type mice achieved by intraperitoneal 5 mg/kg/day glucosamine injection every 24 h for 5 days. The effect of increased O-GlcNAc modification on insulin resistance and ER stress investigated in adipose tissues of glucosamine challenged wild-type mice through regulation of the insulin signaling pathway and unfolded protein response (UPR) elements by western blot. In addition to that, the O-GlcNAc status of the insulin receptor substrate-1 (IRS1) investigated in epididymal and visceral adipose tissues of ob/ob, wild-type and glucosamine challenged mice by immunoprecipitation. Results We found that reduced O-GlcNAc levels in visceral and epididymal adipose tissues of obese and insulin-resistant ob/ob mice, although interestingly we observed that increased O-GlcNAc modification in glucosamine challenged wild-type mice resulted in insulin resistance and ER stress. Furthermore, we demonstrated that the IRS1 was modified with O-GlcNAc in visceral and epididymal adipose tissues in both ob/ob mice and glucosamine-injected mice, and was compatible with the serine phosphorylation of this modification. Conclusion Our results suggest that O-GlcNAcylation of proteins is a crucial factor for intracellular trafficking regulates insulin receptor signaling and UPR depending on the cellular state of insulin resistance.

Mitochondria-associated ER membranes in glucose homeostasis and insulin resistance

2020 ◽  
Vol 319 (6) ◽  
pp. E1053-E1060
Author(s):  
Logan K. Townsend ◽  
Henver S. Brunetta ◽  
Marcelo A. S. Mori
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Glucose Homeostasis ◽  
Calcium Homeostasis ◽  
Adenine Nucleotides ◽  
Current Controversy

Obesity and insulin resistance (IR) are associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction in several tissues. Although for many years mitochondrial and ER function were studied separately, these organelles also connect to produce interdependent functions. Communication occurs at mitochondria-associated ER membranes (MAMs) and regulates lipid and calcium homeostasis, apoptosis, and the exchange of adenine nucleotides, among other things. Recent evidence suggests that MAMs contribute to organelle, cellular, and systemic metabolism. In obesity and IR models, metabolic tissues such as the liver, skeletal muscle, pancreas, and adipose tissue present alterations in MAM structure or function. The purpose of this mini review is to highlight the MAM disruptions that occur in each tissue during obesity and IR and its relationship with glucose homeostasis and IR. We also discuss the current controversy that surrounds MAMs’ role in the development of IR.

scholarly journals Collagen 24 α1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue

2020 ◽  
Vol 21 (16) ◽  
pp. 5738
Author(s):  
Xiong Weng ◽  
De Lin ◽  
Jeffrey T. J. Huang ◽  
Roland H. Stimson ◽  
David H. Wasserman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Resistant ◽  
Global View ◽  
Novel Association ◽  
Visceral Adipose ◽  
Subcutaneous Adipose

Aberrant extracellular matrix (ECM) remodelling in muscle, liver and adipose tissue is a key characteristic of obesity and insulin resistance. Despite its emerging importance, the effective ECM targets remain largely undefined due to limitations of current approaches. Here, we developed a novel ECM-specific mass spectrometry-based proteomics technique to characterise the global view of the ECM changes in the skeletal muscle and liver of mice after high fat (HF) diet feeding. We identified distinct signatures of HF-induced protein changes between skeletal muscle and liver where the ECM remodelling was more prominent in the muscle than liver. In particular, most muscle collagen isoforms were increased by HF diet feeding whereas the liver collagens were differentially but moderately affected highlighting a different role of the ECM remodelling in different tissues of obesity. Moreover, we identified a novel association between collagen 24α1 and insulin resistance in the skeletal muscle. Using quantitative gene expression analysis, we extended this association to the white adipose tissue. Importantly, collagen 24α1 mRNA was increased in the visceral adipose tissue, but not the subcutaneous adipose tissue of obese diabetic subjects compared to lean controls, implying a potential pathogenic role of collagen 24α1 in obesity and type 2 diabetes.

scholarly journals The Role of Endoplasmic Reticulum Stress in Cardiovascular Disease and Exercise

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Junyoung Hong ◽  
Kwangchan Kim ◽  
Jong-Hee Kim ◽  
Yoonjung Park
Keyword(s):  
Cardiovascular Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathways ◽  
Protein Misfolding ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
Apoptosis And Inflammation ◽  
The Unfolded Protein Response

Endoplasmic reticulum (ER) stress, which is highly associated with cardiovascular disease, is triggered by a disturbance in ER function because of protein misfolding or an increase in protein secretion. Prolonged disruption of ER causes ER stress and activation of the unfolded protein response (UPR) and leads to various diseases. Eukaryotic cells respond to ER stress via three major sensors that are bound to the ER membrane: activating transcription factor 6 (ATF6), inositol-requiring protein 1α (IRE1α), and protein kinase RNA-like ER kinase (PERK). Chronic activation of ER stress causes damage in endothelial cells (EC) via apoptosis, inflammation, and oxidative stress signaling pathways. The alleviation of ER stress has recently been accepted as a potential therapeutic target to treat cardiovascular diseases such as heart failure, hypertension, and atherosclerosis. Exercise training is an effective nonpharmacological approach for preventing and alleviating cardiovascular disease. We here review the recent viewing of ER stress-mediated apoptosis and inflammation signaling pathways in cardiovascular disease and the role of exercise in ER stress-associated diseases.

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