CHOP is Dispensable for Exercise-Induced Increases in GDF15

2021 ◽  
Author(s):  
Logan K. Townsend ◽  
Kyle D. Medak ◽  
Alyssa J. Weber ◽  
Hana Dibe ◽  
Hesham Shamshoum ◽  
...  
Keyword(s):  
Er Stress ◽  
Acute Exercise ◽  
Stress Protein ◽  
Whole Body ◽  
Obese Mice ◽  
Stress Markers ◽  
Wide Range ◽  
Underlying Mechanisms ◽  
Exercise Induced ◽  
Deficient Mice

Growth differentiating factor-15 (GDF15) is expressed, and secreted, from a wide range of tissues and serves as a marker of cellular stress. A key transcriptional regulator of this hormone is the endoplasmic reticulum stress protein, CHOP (C/EBP Homologous Protein). Exercise increases GDF15 levels but the underlying mechanisms of this are not known. To test whether CHOP regulates GDF15 during exercise we used various models of altered ER stress. We examined the effects of acute exercise on circulating GDF15 and GDF15 mRNA expression in liver, triceps skeletal muscle, and epididymal white adipose tissue and examined the GDF15 response to acute exercise in lean and high-fat diet-induced obese mice, sedentary and exercise trained mice, and CHOP deficient mice. We found that obesity augments exercise-induced circulating GDF15 although ER stress markers were similar in lean and obese mice. Exercise-induced GDF15 was increased in trained and sedentary mice that ran at the same relative exercise intensity, despite trained mice being protected against increased markers of ER stress. Finally, exercise-induced increases in GDF15 at the tissue and whole-body level were intact in CHOP deficient mice. Together, these results provide evidence that exercise-induced GDF15 expression and secretion occurs independent of ER stress/CHOP.

scholarly journals Acute Tissue Injury Caused by Subcutaneous Fat Biopsies Produces Endoplasmic Reticulum Stress

2009 ◽  
Vol 30 (7) ◽  
pp. 928-928
Author(s):  
Guenther Boden ◽  
Matthew Silviera ◽  
Brian Smith ◽  
Peter Cheung ◽  
Carol Homko
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Tissue Injury ◽  
Subcutaneous Fat ◽  
Whole Body ◽  
Monocyte Chemoattractant Protein 1 ◽  
Homologous Protein ◽  
Stress Markers ◽  
Acute Tissue Injury ◽  
Glucose Regulated Protein

Abstract Background It is not known whether acute tissue injury is associated with endoplasmic reticulum (ER) stress. Objective Our objective was to determine whether open, sc fat biopsies cause ER stress. Approach Five healthy subjects underwent three open sc fat biopsies. The first biopsy, taken from the lateral aspect of a thigh, was followed 4 h later by a second biopsy from the same incision site and a third biopsy from the contralateral leg. Expression markers of ER stress, inflammation, hypoxia, and adipokines were measured in these fat biopsies. In addition, we tested for signs of systemic ER stress and inflammation in plasma and in circulating monocytes. Results mRNA/18s ratios of IL-6, monocyte chemoattractant protein-1, CD-14, hypoxia-induced factor 1-α, the spliced form of Xbox protein-1, glucose-regulated protein 78, CEBP homologous protein, and activating factor-4 were all severalfold higher, whereas mRNA/18s ratios of adiponectin and leptin were lower in fat biopsies taken from the same site 4 h after the first biopsy but were unchanged in the second biopsy that was taken from the contralateral site. The biopsies were not associated with changes in plasma and monocyte IL-6 concentrations or in monocyte ER stress markers. Also, whole-body insulin-stimulated glucose uptake was the same in 15 subjects who had biopsies compared with 15 different subjects who did not. Conclusion Open, sc fat biopsies produced inflammation, hypoxia, ER stress, and decreased expression of adiponectin and leptin. These changes remained confined to the biopsy site for at least 4 h.

scholarly journals 12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response

2012 ◽  
Vol 302 (6) ◽  
pp. E654-E665 ◽  
Author(s):  
Banumathi K. Cole ◽  
Norine S. Kuhn ◽  
Shamina M. Green-Mitchell ◽  
Kendall A. Leone ◽  
Rebekah M. Raab ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Stress Markers ◽  
Deficient Mice

Central obesity is associated with chronic inflammation, insulin resistance, β-cell dysfunction, and endoplasmic reticulum (ER) stress. The 12/15-lipoxygenase enzyme (12/15-LO) promotes inflammation and insulin resistance in adipose and peripheral tissues. Given that obesity is associated with ER stress and 12/15-LO is expressed in adipose tissue, we determined whether 12/15-LO could mediate ER stress signals. Addition of 12/15-LO lipid products 12(S)-HETE and 12(S)-HPETE to differentiated 3T3-L1 adipocytes induced expression and activation of ER stress markers, including BiP, XBP-1, p-PERK, and p-IRE1α. The ER stress inducer, tunicamycin, upregulated ER stress markers in adipocytes with concomitant 12/15-LO activation. Addition of a 12/15-LO inhibitor, CDC, to tunicamycin-treated adipocytes attenuated the ER stress response. Furthermore, 12/15-LO-deficient adipocytes exhibited significantly decreased tunicamycin-induced ER stress. 12/15-LO action involves upregulation of interleukin-12 (IL-12) expression. Tunicamycin significantly upregulated IL-12p40 expression in adipocytes, and IL-12 addition increased ER stress gene expression; conversely, LSF, an IL-12 signaling inhibitor, and an IL-12p40-neutralizing antibody attenuated tunicamycin-induced ER stress. Isolated adipocytes and liver from 12/15-LO-deficient mice fed a high-fat diet revealed a decrease in spliced XBP-1 expression compared with wild-type C57BL/6 mice on a high-fat diet. Furthermore, pancreatic islets from 12/15-LO-deficient mice showed reduced high-fat diet-induced ER stress genes compared with wild-type mice. These data suggest that 12/15-LO activity participates in ER stress in adipocytes, pancreatic islets, and liver. Therefore, reduction of 12/15-LO activity or expression could provide a new therapeutic target to reduce ER stress and downstream inflammation linked to obesity.

scholarly journals Insulin sensitivity variations in apparently healthy Arab male subjects: correlation with insulin and C peptide

2021 ◽  
Vol 9 (2) ◽  
pp. e002039
Author(s):  
Noor Suleiman ◽  
Meis Alkasem ◽  
Shaimaa Hassoun ◽  
Ibrahem Abdalhakam ◽  
Ilham Bettahi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Sensitivity ◽  
Inflammatory Markers ◽  
The Other ◽  
Whole Body ◽  
Oxidative Stress Markers ◽  
C Peptide ◽  
Stress Markers ◽  
Wide Range ◽  
Apparently Healthy

IntroductionDecreased insulin sensitivity occurs early in type 2 diabetes (T2D). T2D is highly prevalent in the Middle East and North Africa regions. This study assessed the variations in insulin sensitivity in normal apparently healthy subjects and the levels of adiponectin, adipsin and inflammatory markers.Research design and methodsA total of 60 participants (aged 18–45, body mass index <28) with a normal oral glucose tolerance test (OGTT) completed hyperinsulinemic-euglycemic clamp (40 mU/m2/min) and body composition test by dual-energy X-ray absorptiometry scan. Blood samples were assayed for glucose, insulin, C peptide, inflammatory markers, oxidative stress markers, adiponectin and adipsin.ResultsThe subjects showed wide variations in the whole-body glucose disposal rate (M value) from 2 to 20 mg/kg/min and were divided into three groups: most responsive (M>12 mg/kg/min, n=17), least responsive (M≤6 mg/kg/min, n=14) and intermediate responsive (M=6.1–12 mg/kg/min, n=29). Insulin and C peptide responses to OGTT were highest among the least insulin sensitive group. Triglycerides, cholesterol, alanine transaminase (ALT) and albumin levels were higher in the least responsive group compared with the other groups. Among the inflammatory markers, C reactive protein (CRP) was highest in the least sensitivity group compared with the other groups; however, there were no differences in the level of soluble receptor for advanced glycation end products and Tumor Necrosis Factor Receptor Superfamily 1B (TNFRS1B). Plasma levels of insulin sensitivity markers, adiponectin and adipsin, and oxidative stress markers, oxidized low-density lipoprotein, total antioxidant capacity and glutathione peroxidase 1, were similar between the groups.ConclusionsA wide range in insulin sensitivity and significant differences in triglycerides, cholesterol, ALT and CRP concentrations were observed despite the fact that the study subjects were homogenous in terms of age, gender and ethnic background, and all had normal screening comprehensive chemistry and normal glucose response to OGTT. The striking differences in insulin sensitivity reflect differences in genetic predisposition and/or environmental exposure. The low insulin sensitivity status associated with increased insulin level may represent an early stage of metabolic abnormality.

scholarly journals Exhaustive acute exercise-induced ER stress is attenuated in IL-6-knockout mice

2019 ◽  
Vol 240 (2) ◽  
pp. 181-193 ◽  
Author(s):  
Ana P Pinto ◽  
Alisson L da Rocha ◽  
Eike B Kohama ◽  
Rafael C Gaspar ◽  
Fernando M Simabuco ◽  
...  
Keyword(s):  
Physical Exercise ◽  
Er Stress ◽  
Knockout Mice ◽  
Acute Exercise ◽  
Stress Proteins ◽  
Serum Levels ◽  
Exercise Protocol ◽  
Caspase 12 ◽  
Exercise Induced ◽  
Eif2 Alpha

The endoplasmic reticulum (ER) stress and inflammation relationship occurs at different levels and is essential for the adequate homeostatic function of cellular systems, becoming harmful when chronically engaged. Intense physical exercise enhances serum levels of interleukin 6 (IL-6). In response to a chronic exhaustive physical exercise protocol, our research group verified an increase of the IL-6 concentration and ER stress proteins in extensor digitorium longus (EDL) and soleus. Based on these results, we hypothesized that IL-6-knockout mice would demonstrate a lower modulation in the ER stress proteins compared to the wild-type mice. To clarify the relationship between exercise-induced IL-6 increased and ER stress, we studied the effects of an acute exhaustive physical exercise protocol on the levels of ER stress proteins in the skeletal muscles of IL-6-knockout (KO) mice. The WT group displayed a higher exhaustion time compared to the IL-6 KO group. After 1 h of the acute exercise protocol, the serum levels of IL-6 and IL-10 were enhanced in the WT group. Independent of the experimental group, the CHOP and cleaved caspase 12/total caspase 12 ratio in EDL as well as ATF6 and CHOP in soleus were sensitive to the acute exercise protocol. Compared to the WT group, the oscillation patterns over time of BiP in EDL and soleus as well as of peIF2-alpha/eIF2-alpha ratio in soleus were attenuated for the IL-6 KO group. In conclusion, IL-6 seems to be related with the ER stress homeostasis, once knockout mice presented attenuation of BiP in EDL and soleus as well as of pEiF2-alpha/EiF2-alpha ratio in soleus after the acute exhaustive physical exercise protocol.

scholarly journals Hypothesized mechanisms through which acute exercise influences episodic memory

2018 ◽  
Vol 105 (4) ◽  
pp. 285-297 ◽  
Author(s):  
PD Loprinzi ◽  
P Ponce ◽  
E Frith
Keyword(s):  
Growth Factor ◽  
Episodic Memory ◽  
Cerebral Circulation ◽  
Acute Exercise ◽  
Memory Function ◽  
Cognitive Outcomes ◽  
Chronic Exercise ◽  
Growth Factor Production ◽  
Underlying Mechanisms ◽  
Exercise Induced

Emerging research demonstrates that exercise is favorably associated with several cognitive outcomes, including episodic memory function. The majority of the mechanistic work describing the underlying mechanisms of this effect has focused on chronic exercise engagement. Such mechanisms include, e.g., chronic exercise-induced neurogenesis, gliogenesis, angiogenesis, cerebral circulation, and growth factor production. Less research has examined the mechanisms through which acute (vs. chronic) exercise subserves episodic memory function. The purpose of this review is to discuss these potential underlying mechanisms, which include, e.g., acute exercise-induced (via several pathways, such as vagus nerve and muscle spindle stimulation) alterations in neurotransmitters, synaptic tagging/capturing, associativity, and psychological attention.

scholarly journals Exercise-Induced Oxidative Stress and the Effects of Antioxidant Intake from a Physiological Viewpoint

Antioxidants ◽  
2018 ◽  
Vol 7 (9) ◽  
pp. 119 ◽  
Author(s):  
Takuji Kawamura ◽  
Isao Muraoka
Keyword(s):  
Oxidative Stress ◽  
Acute Exercise ◽  
Animal Experiments ◽  
Whole Body ◽  
Oxygen Species ◽  
Healthy Individuals ◽  
Redox Biology ◽  
Radical Production ◽  
Antioxidant Intake ◽  
Exercise Induced

It is well established that the increase in reactive oxygen species (ROS) and free radicals production during exercise has both positive and negative physiological effects. Among them, the present review focuses on oxidative stress caused by acute exercise, mainly on evidence in healthy individuals. This review also summarizes findings on the determinants of exercise-induced oxidative stress and sources of free radical production. Moreover, we outline the effects of antioxidant supplementation on exercise-induced oxidative stress, which have been studied extensively. Finally, the following review briefly summarizes future tasks in the field of redox biology of exercise. In principle, this review covers findings for the whole body, and describes human trials and animal experiments separately.

scholarly journals Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14

2019 ◽  
Vol 116 (43) ◽  
pp. 21732-21738 ◽  
Author(s):  
Bin Liu ◽  
Zhijian Zhang ◽  
Yanyun Hu ◽  
Yan Lu ◽  
Duanzhuo Li ◽  
...  
Keyword(s):  
Er Stress ◽  
Metabolic Diseases ◽  
Low Grade ◽  
Deubiquitinating Enzyme ◽  
Obese Mice ◽  
Hepatic Gluconeogenesis ◽  
Regulatory Pathways ◽  
Underlying Mechanisms ◽  
The Stability ◽  
Glucose Output

Endoplasmic reticulum (ER) stress plays an important role in metabolic diseases like obesity and type 2 diabetes mellitus (T2DM), although the underlying mechanisms and regulatory pathways remain to be elucidated. Here, we induced chronic low-grade ER stress in lean mice to levels similar to those in high-fat diet (HFD)–fed obese mice and found that it promoted hyperglycemia due to enhanced hepatic gluconeogenesis. Mechanistically, sustained ER stress up-regulated the deubiquitinating enzyme ubiquitin-specific peptidase 14 (USP14), which increased the stability and levels of 3′,5′-cyclic monophosphate–responsive element binding (CREB) protein (CBP) to enhance glucagon action and hepatic gluconeogenesis. Exogenous overexpression of USP14 in the liver significantly increased hepatic glucose output. Consistent with this, liver-specific knockdown of USP14 abrogated the effects of ER stress on glucose metabolism, and also improved hyperglycemia and glucose intolerance in obese mice. In conclusion, our findings show a mechanism underlying ER stress-induced disruption of glucose homeostasis, and present USP14 as a potential therapeutic target against T2DM.

PGC-1α mediates exercise-induced skeletal muscle VEGF expression in mice

2009 ◽  
Vol 297 (1) ◽  
pp. E92-E103 ◽  
Author(s):  
Lotte Leick ◽  
Ylva Hellsten ◽  
Joachim Fentz ◽  
Stine S. Lyngby ◽  
Jørgen F. P. Wojtaszewski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Protein Expression ◽  
Protein Content ◽  
Acute Exercise ◽  
Whole Body ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Exercise Induced ◽  
Vegf Protein

The aim of the present study was to test the hypothesis that PGC-1α is required for exercise-induced VEGF expression in both young and old mice and that AMPK activation leads to increased VEGF expression through a PGC-1α-dependent mechanism. Whole body PGC-1α knockout (KO) and littermate wild-type (WT) mice were submitted to either 1) 5 wk of exercise training, 2) lifelong (from 2 to 13 mo of age) exercise training in activity wheel, 3) a single exercise bout, or 4) 4 wk of daily subcutaneous AICAR or saline injections. In skeletal muscle of PGC-1α KO mice, VEGF protein expression was ∼60–80% lower and the capillary-to-fiber ratio ∼20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1α KO mice, but acute exercise and AICAR treatment increased the VEGF mRNA content in WT mice only. Exercise training of young mice increased skeletal muscle VEGF protein expression ∼50% in WT mice but with no effect in PGC-1α KO mice. Furthermore, a training-induced prevention of an age-associated decline in VEGF protein content was observed in WT but not in PGC-1α KO muscles. In addition, repeated AICAR treatments increased skeletal muscle VEGF protein expression ∼15% in WT but not in PGC-1α KO mice. This study shows that PGC-1α is essential for exercise-induced upregulation of skeletal muscle VEGF expression and for a training-induced prevention of an age-associated decline in VEGF protein content. Furthermore, the findings suggest an AMPK-mediated regulation of VEGF expression through PGC-1α.

scholarly journals Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Carla Igual Gil ◽  
Mario Ost ◽  
Juliane Kasch ◽  
Sara Schumann ◽  
Sarah Heider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Acute Exercise ◽  
Treadmill Running ◽  
Exercise Stress ◽  
Metabolic Phenotype ◽  
Obese Mice ◽  
Active Lifestyle ◽  
Post Exercise ◽  
Stress Markers

AbstractPhysical activity is an important contributor to muscle adaptation and metabolic health. Growth differentiation factor 15 (GDF15) is established as cellular and nutritional stress-induced cytokine but its physiological role in response to active lifestyle or acute exercise is unknown. Here, we investigated the metabolic phenotype and circulating GDF15 levels in lean and obese male C57Bl/6J mice with long-term voluntary wheel running (VWR) intervention. Additionally, treadmill running capacity and exercise-induced muscle gene expression was examined in GDF15-ablated mice. Active lifestyle mimic via VWR improved treadmill running performance and, in obese mice, also metabolic phenotype. The post-exercise induction of skeletal muscle transcriptional stress markers was reduced by VWR. Skeletal muscle GDF15 gene expression was very low and only transiently increased post-exercise in sedentary but not in active mice. Plasma GDF15 levels were only marginally affected by chronic or acute exercise. In obese mice, VWR reduced GDF15 gene expression in different tissues but did not reverse elevated plasma GDF15. Genetic ablation of GDF15 had no effect on exercise performance but augmented the post exercise expression of transcriptional exercise stress markers (Atf3, Atf6, and Xbp1s) in skeletal muscle. We conclude that skeletal muscle does not contribute to circulating GDF15 in mice, but muscle GDF15 might play a protective role in the exercise stress response.

scholarly journals Plant Bioactive Molecules Reduces Endoplasmic Reticulum Stress in Liver and Adipose Tissue of Obese Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 482-482
Author(s):  
Ivan Torre-Villalvazo ◽  
Armando Tovar ◽  
Claudia Tovar-Palacio ◽  
Nimbe Torres ◽  
Erik Alejandro Torre ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Low Dose ◽  
Control Diet ◽  
Bioactive Molecules ◽  
Obese Mice ◽  
Funding Sources ◽  
Stress Markers

Abstract Objectives To determine if diferent plant bioactive compounds can ammelirate endoplasmic reticulum stress markers in liver and adipose tissue of obese mice and mice administered with a low dose of tunicamicin. Methods C57BL6 mice were fed a control diet (7% fat) or a high-fat diet (21% fat) with and without genistein or resveratrol supplementation (0.1%) for 12 weeks. Pharmacologic ER stress was induced in mice fed the control diet by an ip injection of a low dose of tunicamycin and euthanized 8 or 24 h after tunicamycin administration. Adipose tissues and liver were harvested to determine the abundance of ER stress markers by western blot and real time PCR. Results Genistein and resveratrol reduced the abundance of phospho JNK and phospho PERK in liver and subcutaneous adipose tissue of obese mice and lean mice administered with tunicamycin. Both polyphenols increased the mRNA abundance of XBP1s and BiP and reduced that of CHOP in both organs. These changes in proten phosphorylation and gene expression were accompanied with reduced hepatic steatosis and adipocyte hypertrophy. Conclusions The supplementation with plant polyphenols such as genistein or resveratrol reduced ER stress markers in liver and adipose tissue of obese mice and lean mice administerd with tunicamycin. Funding Sources This work is supported by a grant from CONACYT, Mexico to ITV Grant No. A1-S-41,077.

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