Mitochondria-associated ER membranes in glucose homeostasis and insulin resistance

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.

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Different Expression of Mitochondrial and Endoplasmic Reticulum Stress Genes in Epicardial Adipose Tissue Depends on Coronary Atherosclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms22094538 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4538

Author(s):

Helena Kratochvílová ◽

Miloš Mráz ◽

Barbora J. Kasperová ◽

Daniel Hlaváček ◽

Jakub Mahrík ◽

...

Keyword(s):

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Adipose Tissue ◽

Cardiac Surgery ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Mrna Expression ◽

Coronary Atherosclerosis ◽

Stress Genes ◽

Valvular Surgery

The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery; mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis.

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Fenofibrate Ameliorates Insulin Resistance of Lipoprotein Lipase Knockout Heterozygous Mice

10.21203/rs.2.22680/v1 ◽

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.

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Oleate Blocks Palmitate-Induced Abnormal Lipid Distribution, Endoplasmic Reticulum Expansion and Stress, and Insulin Resistance in Skeletal Muscle

Endocrinology ◽

10.1210/en.2010-1369 ◽

2011 ◽

Vol 152 (6) ◽

pp. 2206-2218 ◽

Cited By ~ 98

Author(s):

Gong Peng ◽

Linghai Li ◽

Yanbo Liu ◽

Jing Pu ◽

Shuyan Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Fatty Acids ◽

Endoplasmic Reticulum ◽

Insulin Sensitivity ◽

Er Stress ◽

Molecular Mechanisms ◽

Dietary Fatty Acids ◽

Akt Phosphorylation ◽

Stress Relieving

Pathological elevation of plasma fatty acids reduces insulin sensitivity. Although several regulation pathways have been reported, the molecular mechanisms of insulin sensitivity remain elusive, especially in skeletal muscle where most glucose is consumed. This study focuses on how two major dietary fatty acids affect insulin signaling in skeletal muscle cells. Palmitic acid (PA) not only reduced insulin-stimulated phosphorylation of Akt but also induced endoplasmic reticulum (ER) expansion and ER stress. Relieving ER stress using 4-phenyl butyric acid blocked PA-mediated protein kinase R-like ER kinase phosphorylation and ER expansion and reversed the inhibitory effect of PA on insulin-stimulated Akt phosphorylation. Importantly, oleic acid (OA) could also recover PA-reduced Akt phosphorylation and abolish both PA-mediated ER expansion and ER stress. The competition between these two fatty acids was further verified in rat skeletal muscle using venous fatty acid infusion. 3H-labeled PA was converted mainly to active lipids (phospholipids and diacylglycerol) in the absence of OA, but to triacylglycerol in the presence of OA. Subcellular triacylglycerol and adipocyte differentiation-related protein from PA-treated cells cofractionated with the ER in the absence of OA but switched to the low-density fraction in the presence of OA. Taken together, these data suggest that the PA-mediated lipid composition and localization may cause ER expansion and consequently cause ER stress and insulin resistance in skeletal muscle.

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Fibroblast growth factor 21 reverses suppression of adiponectin expression via inhibiting endoplasmic reticulum stress in adipose tissue of obese mice

Experimental Biology and Medicine ◽

10.1177/1535370216677354 ◽

2016 ◽

Vol 242 (4) ◽

pp. 441-447 ◽

Cited By ~ 8

Author(s):

Qinyue Guo ◽

Lin Xu ◽

Jiali Liu ◽

Huixia Li ◽

Hongzhi Sun ◽

...

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Growth Factor ◽

Er Stress ◽

Insulin Signaling ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Obese Mice

Fibroblast growth factor 21 (FGF21) has recently emerged as a novel endocrine hormone involved in the regulation of glucose and lipid metabolism. However, the exact mechanisms whereby FGF21 mediates insulin sensitivity remain not fully understood. In the present study, FGF21was administrated in high-fat diet-induced obese mice and tunicamycin-induced 3T3-L1 adipocytes, and metabolic parameters, endoplasmic reticulum (ER) stress indicators, and insulin signaling molecular were assessed by Western blotting. The administration of FGF21 in obese mice reduced body weight, blood glucose and serum insulin, and increased insulin sensitivity, resulting in alleviation of insulin resistance. Meanwhile, FGF21 treatment reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress in adipose tissue of obese mice. Additionally, suppression of ER stress via the ER stress inhibitor tauroursodeoxycholic acid increased adiponectin expression and improved insulin resistance in obese mice and in tunicamycin-induced adipocytes. In conclusion, our results showed that the administration of FGF21 reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress under the condition of insulin resistance, demonstrating the causative role of ER stress in downregulating adiponectin levels.

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Adipose Tissue Inflammation Is Directly Linked to Obesity-Induced Insulin Resistance, while Gut Dysbiosis and Mitochondrial Dysfunction Are Not Required

Function ◽

10.1093/function/zqaa013 ◽

2020 ◽

Vol 1 (2) ◽

Cited By ~ 1

Author(s):

Heather L Petrick ◽

Kevin P Foley ◽

Soumaya Zlitni ◽

Henver S Brunetta ◽

Sabina Paglialunga ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Mitochondrial Dysfunction ◽

Intestinal Microbiome ◽

Mitochondrial Bioenergetics ◽

Obese Mice ◽

Gut Dysbiosis ◽

Intestinal Dysbiosis ◽

Adipose Inflammation

Abstract Obesity is associated with adipose tissue hypertrophy, systemic inflammation, mitochondrial dysfunction, and intestinal dysbiosis. Rodent models of high-fat diet (HFD)-feeding or genetic deletion of multifunctional proteins involved in immunity and metabolism are often used to probe the etiology of obesity; however, these models make it difficult to divorce the effects of obesity, diet composition, or immunity on endocrine regulation of blood glucose. We, therefore, investigated the importance of adipose inflammation, mitochondrial dysfunction, and gut dysbiosis for obesity-induced insulin resistance using a spontaneously obese mouse model. We examined metabolic changes in skeletal muscle, adipose tissue, liver, the intestinal microbiome, and whole-body glucose control in spontaneously hyperphagic C57Bl/6J mice compared to lean littermates. A separate subset of lean and obese mice was subject to 8 weeks of obesogenic HFD feeding, or to pair feeding of a standard rodent diet. Hyperphagia, obesity, adipose inflammation, and insulin resistance were present in obese mice despite consuming a standard rodent diet, and these effects were blunted with caloric restriction. However, hyperphagic obese mice had normal mitochondrial respiratory function in all tissues tested and no discernable intestinal dysbiosis relative to lean littermates. In contrast, feeding mice an obesogenic HFD altered the composition of the gut microbiome, impaired skeletal muscle mitochondrial bioenergetics, and promoted poor glucose control. These data show that adipose inflammation and redox stress occurred in all models of obesity, but gut dysbiosis and mitochondrial respiratory dysfunction are not always required for obesity-induced insulin resistance. Rather, changes in the intestinal microbiome and mitochondrial bioenergetics may reflect physiological consequences of HFD feeding.

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

Molecular and Cellular Biology ◽

10.1128/mcb.00921-15 ◽

2015 ◽

pp. MCB.00921-15 ◽

Cited By ~ 1

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.

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Nicorandil attenuates high glucose-induced insulin resistance by suppressing oxidative stress-mediated ER stress PERK signaling pathway

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001884 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001884

Author(s):

Zhongwei Liu ◽

Haitao Zhu ◽

Chunhui He ◽

Ting He ◽

Shuo Pan ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Protein Kinase ◽

Glucose Tolerance ◽

Er Stress ◽

High Glucose ◽

Muscle Cells ◽

Skeletal Muscle Cells

IntroductionGlucose-induced insulin resistance is a typical character of diabetes. Nicorandil is now widely used in ischemic heart disease. Nicorandil shows protective effects against oxidative and endoplasmic reticulum (ER) stress, which are involved in insulin resistance. Here, we investigated mechanisms of nicorandil’s novel pharmacological activity on insulin resistance in diabetes.Research design and methodsNicorandil was administrated to streptozotocin-induced animals with diabetes and high glucose exposed skeletal muscle cells. Insulin resistance and glucose tolerance were evaluated. Molecular mechanisms concerning oxidative stress, ER stress signaling activation and glucose uptake were assessed.ResultsNicorandil attenuated high glucose-induced insulin resistance without affecting fasting blood glucose and glucose tolerance in whole body and skeletal muscle in rats with diabetes. Nicorandil treatment suppressed protein kinase C/nicotinamide adenine dinucleotide phosphate oxidases system activities by reducing cytoplasmic free calcium level in skeletal muscle cells exposed to high glucose. As a result, the oxidative stress-mediated ER stress protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α/activating transcription factor 4/CEBP homologous protein/tribbles homolog (TRB)3 signaling pathway activation was inhibited. Nicorandil downregulated expression of TRB3 and thus facilitated Akt phosphorylation in response to insulin stimulation, leading to glucose transporter4 plasma membrane translocation which promoted glucose uptake capability of skeletal muscle cells.ConclusionsBy reducing cytoplasmic calcium, nicorandil alleviated high glucose-induced insulin resistance by inhibiting oxidative stress-mediated ER stress PERK pathway.

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Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells

Antioxidants ◽

10.3390/antiox9080710 ◽

2020 ◽

Vol 9 (8) ◽

pp. 710

Author(s):

Anastasia Thoma ◽

Max Lyon ◽

Nasser Al-Shanti ◽

Gareth A. Nye ◽

Robert G. Cooper ◽

...

Keyword(s):

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Muscle Weakness ◽

Ros Generation ◽

Transcriptional Level ◽

Mrna Levels ◽

Human Skeletal Muscle Cells ◽

The Impact

Maladaptive endoplasmic reticulum (ER) stress is associated with modified reactive oxygen species (ROS) generation and mitochondrial abnormalities; and is postulated as a potential mechanism involved in muscle weakness in myositis, an acquired autoimmune neuromuscular disease. This study investigates the impact of ROS generation in an in vitro model of ER stress in skeletal muscle, using the ER stress inducer tunicamycin (24 h) in the presence or absence of a superoxide dismutase/catalase mimetic Eukarion (EUK)-134. Tunicamycin induced maladaptive ER stress, which was mitigated by EUK-134 at the transcriptional level. ER stress promoted mitochondrial dysfunction, described by substantial loss of mitochondrial membrane potential, as well as a reduction in respiratory control ratio, reserve capacity, phosphorylating respiration, and coupling efficiency, which was ameliorated by EUK-134. Tunicamycin induced ROS-mediated biogenesis and fusion of mitochondria, which, however, had high propensity of fragmentation, accompanied by upregulated mRNA levels of fission-related markers. Increased cellular ROS generation was observed under ER stress that was prevented by EUK-134, even though no changes in mitochondrial superoxide were noticeable. These findings suggest that targeting ROS generation using EUK-134 can amend aspects of ER stress-induced changes in mitochondrial dynamics and function, and therefore, in instances of chronic ER stress, such as in myositis, quenching ROS generation may be a promising therapy for muscle weakness and dysfunction.

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CYP2J3 Gene Delivery Up-Regulated Adiponectin Expression via Reduced Endoplasmic Reticulum Stress in Adipocytes

Endocrinology ◽

10.1210/en.2012-2012 ◽

2013 ◽

Vol 154 (5) ◽

pp. 1743-1753 ◽

Cited By ~ 20

Author(s):

Xizhen Xu ◽

Ling Tu ◽

Wenjing Feng ◽

Ben Ma ◽

Rui Li ◽

...

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Adipose Tissue ◽

Gene Delivery ◽

Er Stress ◽

Gene Transfection ◽

Resistance Index ◽

Tolerance Test ◽

Downstream Signaling

Abstract Ample evidences demonstrate that cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play crucial and diverse roles in cardiovascular homeostasis. We and others have identified that EETs exert a beneficial role on insulin resistance and diabetes. This study investigated the effects of CYP2J3 epoxygenase gene delivery on adiponectin expression in rats treated with high-fat (HF) diet. CYP2J3 gene delivery in vivo increased EET generation, enhanced adiponectin expression and secretion and accompanied by activation of adiponectin downstream signaling, and decreased insulin resistance as determined by plasma insulin levels, insulin resistance index and glucose tolerance test, as well as phosphorylation of protein kinase B in both liver and muscle. Furthermore, CYP2J3 overexpression prevented HF diet-induced endoplasmic reticulum (ER) stress in adipose tissue of rats. Also, CYP2J3 gene transfection and exogenous administration of EETs inhibited thapsigargin-induced ER stress with increased adiponectin expression and secretion in differentiated 3T3-L1 adipocytes. Thus, CYP2J3 gene delivery up-regulated adiponectin expression and excretion in adipose tissue of rats treated with HF diet through inhibition of ER stress, which can decrease adiponectin expression. These results further highlight the beneficial roles of the CYP epoxygenase 2J3 and its metabolites EETs on adiponectin expression and secretion.

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Zinc, Selenium and Chromium Supplementation Improves Insulin Resistance by Preventing Hepatic Endoplasmic Reticulum Stress in Diet-Induced Gestational Diabetes Rats

Current Developments in Nutrition ◽

10.1093/cdn/nzab042_015 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 548-548

Author(s):

Xueqiong Yao ◽

Xuefeng Yang

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Protein Kinase ◽

Gestational Diabetes ◽

Er Stress ◽

Glucose Homeostasis ◽

Insulin Signaling ◽

Adverse Outcomes ◽

Lactation Period ◽

Sprague Dawley

Abstract Objectives Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and results in adverse outcomes for pregnant women and their offspring. Endoplasmic reticulum (ER) stress is associated with insulin resistance and implicates in the development of GDM. Zinc, selenium and chromium have been shown to maintain glucose homeostasis via multiple mechanisms, but how these trace elements affect the insulin resistance and ER stress in GDM are largely unknown. Methods A GDM rat model was induced by feeding female Sprague-Dawley (SD) rats a high-fat (45%) and sucrose (HFS) diet, while zinc (10 mg/kg.bw), selenium (20 ug/kg.bw), chromium (20 ug/kg.bw) were daily supplemented alone or in combination from 6 weeks before mating to the end of lactation period. Maternal metabolic parameters, hepatic ER stress and insulin signaling were analyzed. Results The results showed that zinc, selenium and chromium supplementation dramatically alleviated HFS-induced glucose intolerance and oxidative stress during entire experiment period. Hepatic ER stress as well as the unfolded protein response (UPR) was activated in GDM rats, characterized by the up-regulation of glucose-regulated protein 78 (GRP78), phosphorylated the protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), and the inositol-requiring enzyme 1α (p-IRE1α). Zinc, selenium and chromium supplementation significantly prevented this activation, by which contributes to the promotion of the phosphorylated protein kinase B (p-AKT) related insulin signaling and maintenance of glucose homeostasis. Conclusions Zinc, selenium and chromium supplementation may be a promising way to prevent the development of GDM by alleviating hepatic ER stress. Funding Sources This work was financially supported by the Angel Nutritech Nutrition Fund (AF2017003) and the National Natural Science Foundation of China (NSFC, 81373006 and 81973043).

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