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

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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Mitochondria-associated ER membranes in glucose homeostasis and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00271.2020 ◽

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.

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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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Glycoursodeoxycholic Acid Ameliorates Diet-induced Metabolic Disorders with Inhibiting Endoplasmic Reticulum Stress

Clinical Science ◽

10.1042/cs20210198 ◽

2021 ◽

Author(s):

Lele Cheng ◽

Tao Chen ◽

Manyun Guo ◽

Peining Liu ◽

Xiangrui Qiao ◽

...

Keyword(s):

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Bile Acid ◽

Er Stress ◽

Hepatic Steatosis ◽

Metabolic Disorders ◽

Stool Samples ◽

Glycoursodeoxycholic Acid

Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. In the present study, metabolomic analysis of 163 serum and stool samples of our metabolic disease cohort was performed and we identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, were decreased in both serum and stool samples from patients with hyperglycemia. RNA-sequencing and quantitative PCR results indicated that GUDCA alleviated endoplasmic reticulum (ER) stress in livers of high fat diet (HFD)-fed mice without alteration of liver metabolism. In vitro, GUDCA reduced palmitic acid induced-ER stress and -apoptosis, as well as stabilized calcium homeostasis. In vivo, GUDCA exerted effects on amelioration of HFD-induced insulin resistance and hepatic steatosis. In parallel, ER stress and apoptosis were decreased in GUDCA-treated mice as compared to vehicle-treated mice in liver. These findings demonstrate that reduced GUDCA is an indicator of hyperglycemia. Supplementation of GUDCA could be an option for the treatment of diet-induced metabolic disorders, including insulin resistance and hepatic steatosis, with inhibiting ER stress.

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Treatment With Atrial Natriuretic Peptide Induces Adipose Tissue Browning and Exerts Thermogenic Actions in Vivo.

10.21203/rs.3.rs-527068/v1 ◽

2021 ◽

Author(s):

Haruka Kimura ◽

Tomohisa Nagoshi ◽

Yuhei Oi ◽

Akira Yoshii ◽

Yoshiro Tanaka ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Hepatic Steatosis ◽

Cold Exposure ◽

Lipid Droplets ◽

Tolerance Test ◽

Adipose Tissues ◽

Brown Adipose ◽

Tissue Browning

Abstract Background: Although natriuretic peptides (NPs) classically act on the renal and cardiovascular systems, increasing evidence suggests that NPs also largely coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism. We recently reported that A-type NP (ANP) raises the intracellular temperature in cultured adipocytes in a low-temperature-sensitive manner. We herein investigated whether or not exogenous ANP treatment exerts a significant impact on adipose tissues in vivo using diet-induced obese mice.Methods and Results: C57BL/6 mice fed a high-fat diet (HFD) or normal-fat diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously via osmotic pump for another 3 weeks (0.5 μg/kg/min). The intraperitoneal glucose tolerance test and insulin tolerance test showed that ANP treatment significantly ameliorated HFD-induced insulin resistance. Histological analyses revealed that HFD increased the brown adipose tissue (BAT) cell size with the accumulation of lipid droplets (whitening), which was suppressed by ANP treatment (re-browning). Furthermore, HFD induced enlarged lipid droplets in inguinal white adipose tissue (iWAT), crown-like structures in epididymal WAT (eWAT), and hepatic steatosis, all of which were substantially attenuated by ANP treatment. Likewise, ANP treatment markedly increased the expression of uncoupling protein-1 (UCP1), a specific marker of BAT, in iWAT (browning). ANP also further increased the UCP1 expression in BAT with an NFD. Accordingly, the cold tolerance test (at 4 °C for 4 h) demonstrated that the ANP-treated mice were tolerant to cold exposure.Conclusions: Exogenous ANP administration ameliorates HFD-induced insulin resistance by attenuating hepatic steatosis as well as by inducing adipose tissue browning (activation of the adipose tissue thermogenic program), leading to in vivo thermogenesis during cold exposure.

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Mechanisms of disordered neurodegenerative function: concepts and facts about the different roles of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)

Reviews in the Neurosciences ◽

10.1515/revneuro-2017-0071 ◽

2018 ◽

Vol 29 (4) ◽

pp. 387-415 ◽

Cited By ~ 3

Author(s):

Yasmeen M. Taalab ◽

Nour Ibrahim ◽

Ahmed Maher ◽

Mubashir Hassan ◽

Wael Mohamed ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Protein Kinase ◽

Neurodegenerative Diseases ◽

Er Stress ◽

Protein Misfolding ◽

Disease Models ◽

Downstream Signaling ◽

Unfolded Protein

AbstractNeurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis. Evidences fromin vitroandin vivodisease models indicate that disruption of ER homeostasis causes abnormal protein aggregation that leads to synaptic and neuronal dysfunction. However, the exact mechanism by which it contributes to disease progression and pathophysiological changes remains vague. Downstream signaling pathways of UPR are fully integrated, yet with diverse unexpected outcomes in different disease models. Three well-identified ER stress sensors have been implicated in UPR, namely, inositol requiring enzyme 1, protein kinase RNA-activated-like ER kinase (PERK), and activating transcription factor 6. Although it cannot be denied that each of the involved stress sensor initiates a distinct downstream signaling pathway, it becomes increasingly clear that shared pathways are crucial in determining whether or not the UPR will guide the cells toward adaptive prosurvival or proapoptotic responses. We review a body of work on the mechanism of neurodegenerative diseases based on oxidative stress and cell death pathways with emphasis on the role of PERK.

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Gpr1 is an active chemerin receptor influencing glucose homeostasis in obese mice

Journal of Endocrinology ◽

10.1530/joe-14-0069 ◽

2014 ◽

Vol 222 (2) ◽

pp. 201-215 ◽

Cited By ~ 52

Author(s):

Jillian L Rourke ◽

Shanmugam Muruganandan ◽

Helen J Dranse ◽

Nichole M McMullen ◽

Christopher J Sinal

Keyword(s):

Adipose Tissue ◽

Glucose Homeostasis ◽

Stromal Vascular Fraction ◽

Tolerance Test ◽

Glucose Levels ◽

Brown Adipose ◽

Elevated Glucose ◽

And Function ◽

G Protein Coupled

Chemerin is an adipose-derived signaling protein (adipokine) that regulates adipocyte differentiation and function, immune function, metabolism, and glucose homeostasis through activation of chemokine-like receptor 1 (CMKLR1). A second chemerin receptor, G protein-coupled receptor 1 (GPR1) in mammals, binds chemerin with an affinity similar to CMKLR1; however, the function of GPR1 in mammals is essentially unknown. Herein, we report that expression of murineGpr1mRNA is high in brown adipose tissue and white adipose tissue (WAT) and skeletal muscle. In contrast to chemerin (Rarres2) andCmklr1,Gpr1expression predominates in the non-adipocyte stromal vascular fraction of WAT. Heterozygous and homozygousGpr1-knockout mice fed on a high-fat diet developed more severe glucose intolerance than WT mice despite having no difference in body weight, adiposity, or energy expenditure. Moreover, mice lackingGpr1exhibited reduced glucose-stimulated insulin levels and elevated glucose levels in a pyruvate tolerance test. This study is the first, to our knowledge, to report the effects ofGpr1deficiency on adiposity, energy balance, and glucose homeostasisin vivo. Moreover, these novel results demonstrate that GPR1 is an active chemerin receptor that contributes to the regulation of glucose homeostasis during obesity.

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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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Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01915-9 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Changhong Li ◽

Kui Zhang ◽

Guangzhao Pan ◽

Haoyan Ji ◽

Chongyang Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Endoplasmic Reticulum ◽

Cell Growth ◽

Er Stress ◽

Cancer Cells ◽

Tumor Xenograft ◽

Anticancer Activities ◽

Colorectal Cancer Cells

Abstract Background Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated. Methods In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo. Results Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models. Conclusions Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00373.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. E654-E665 ◽

Cited By ~ 35

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.

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Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice

Journal of Endocrinology ◽

10.1677/joe.0.1670107 ◽

2000 ◽

Vol 167 (1) ◽

pp. 107-115 ◽

Cited By ~ 98

Author(s):

J Shao ◽

H Yamashita ◽

L Qiao ◽

JE Friedman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Transporter ◽

Kinase Activity ◽

Glycogen Synthase ◽

Glut4 Translocation ◽

Akt Kinase ◽

Insulin Signal Transduction ◽

Kinase Pathway

Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.

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