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

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 CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice

2019 ◽  
Vol 317 (6) ◽  
pp. E973-E983 ◽  
Author(s):  
Annie Hasib ◽  
Chandani K. Hennayake ◽  
Deanna P. Bracy ◽  
Aimée R. Bugler-Lamb ◽  
Louise Lantier ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
High Fat Diet ◽  
Critical Role ◽  
Chow Diet ◽  
Wild Type ◽  
High Fat ◽  
Insulin Resistant ◽  
Beneficial Effects

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

Abstract 17649: Inhibition of Src Homology 2 Domain-containing Phosphatase 1 (SHP-1) Increases Insulin Sensitivity in High-fat Diet-induced Insulin Resistant C57black6 Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Janine Krüger ◽  
Markus Dagnell ◽  
Philipp Stawowy ◽  
Evren Caglayan ◽  
Arne Östman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
High Fat ◽  
Insulin Resistant ◽  
Cardiovascular Morbidity And Mortality

Background: Insulin resistance plays a crucial role in the development of type 2 diabetes, and exerts great impact on vascular inflammation and remodeling. At the molecular level a post-insulin receptor (IR) defect in insulin signaling has been suggested to contribute to insulin resistance. IR signaling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). The precise role of PTPs in insulin resistance, however, has not been explored. Results: Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat) to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD mice were treated with PTP-inhibitors for additional 6 weeks. Mice under HFD exhibited a significant increase in body weight as well as decreased respiratory quotient and adiponectin levels, and were characterized by impaired insulin- and glucose tolerance. Organ-based gene expression analyses in insulin-resistant mice demonstrated upregulation of SHP-1, PTP1B, LAR, and DEP-1 in insulin-sensitive organs. SHP-1 was further explored in vitro. Insulin stimulation in murine liver cells induced site-selective hyper-phosphorylation at IR tyrosine-sites Y1158, and Y1361 after inhibition of SHP-1. Furthermore, SHP-1 impairment time-dependently enhanced insulin-induced Akt- and Erk-phosphorylation, and resulted in elevated glucose uptake in skeletal muscle cells. Administration of a SHP-1 inhibitor (Sodium Stibogluconate) and a brought pan-PTP inhibitor (BMOV) in HFD mice led to improvement of both insulin- and glucose tolerance. In accordance, PTP-activity was significantly impaired in epididymal fat, skeletal muscle, and liver under BMOV treatment, being confirmed by reduced ex vivo dephosphorylation of a radioactive labelled peptide (AEEEIYGEFEAKKKK). Finally, BMOV- and SHP-1 treatment also resulted in reduced body weight. Conclusions: IR-antagonizing PTPs were organ-specifically regulated in insulin resistance. The results indicate a central role of PTPs and, in particular, of SHP-1 as endogenous antagonists of the IR. Taken together targeting PTPs led to beneficial effects in insulin resistance, and may thus improve metabolic diseases as well as cardiovascular morbidity and mortality.

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 Intramuscular Injection of miR-1 Reduces Insulin Resistance in Obese Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Alice C. Rodrigues ◽  
Alexandre R. Spagnol ◽  
Flávia de Toledo Frias ◽  
Mariana de Mendonça ◽  
Hygor N. Araújo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Insulin Sensitivity ◽  
Mitochondrial Respiration ◽  
High Fat Diet ◽  
C2c12 Cells ◽  
High Fat ◽  
Spare Capacity

The role of microRNAs in metabolic diseases has been recognized and modulation of them could be a promising strategy to treat obesity and obesity-related diseases. The major purpose of this study was to test the hypothesis that intramuscular miR-1 precursor replacement therapy could improve metabolic parameters of mice fed a high-fat diet. To this end, we first injected miR-1 precursor intramuscularly in high-fat diet-fed mice and evaluated glucose tolerance, insulin sensitivity, and adiposity. miR-1-treated mice did not lose weight but had improved insulin sensitivity measured by insulin tolerance test. Next, using an in vitro model of insulin resistance by treating C2C12 cells with palmitic acid (PA), we overexpressed miR-1 and measured p-Akt content and the transcription levels of a protein related to fatty acid oxidation. We found that miR-1 could not restore insulin sensitivity in C2C12 cells, as indicated by p-Akt levels and that miR-1 increased expression of Pgc1a and Cpt1b in PA-treated cells, suggesting a possible role of miR-1 in mitochondrial respiration. Finally, we analyzed mitochondrial oxygen consumption in primary skeletal muscle cells treated with PA and transfected with or without miR-1 mimic. PA-treated cells showed reduced basal respiration, oxygen consumption rate-linked ATP production, maximal and spare capacity, and miR-1 overexpression could prevent impairments in mitochondrial respiration. Our data suggest a role of miR-1 in systemic insulin sensitivity and a new function of miR-1 in regulating mitochondrial respiration in skeletal muscle.

scholarly journals Fenofibrate Alleviates Insulin Resistance and Hepatic Steatosis via Modulation of let-7/ SERCA2b Axis

2020 ◽  
Author(s):  
Dan Zhang ◽  
Shan-zhuang Niu ◽  
Yi-cheng Ma ◽  
Bo Zhou ◽  
Yi Deng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Luciferase Reporter ◽  
Control Group ◽  
Chow Diet ◽  
High Fat ◽  
Alcoholic Fatty Liver

Abstract Background: Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist, which is widely used in clinical practice to effectively ameliorates the development of NAFLD. However, the molecular mechanism remains largely unknown, the present study aimed to investigate the role and specific mechanism of fenofibrate on lipid metabolism disorders associated diseases.Methods: The male C57BL6/J mice were divided into 3 groups, the mice in control group (n=10) were fed with normal chow diet, and the mice in HFD-fed group (n =10) were fed with a high fat diet (HFD) for 14 weeks. For the fenofibrate +HFD-fed group (n =10), the mice fed HFD were orally gavaged with fenofibrate (40 mg/kg) daily for the last 4 weeks. Body weight and hip width were measured. Macrosteatosis and fat deposition in the liver were measured by H&E staining and Oil red O staining individually. The levels of serum and hepatic triglyceride were measured, and HOMA-IR, HOMA-ISI were analyzed. The levels of SCD-1, Bip, CHOP and SERCA2b were measured by western blotting. The expression of let-7 were analyzed by qPCR, and the complementarity between the 3′-UTR of SERCA2b gene and let-7 was measured by luciferase reporter assay.Results: Fenofibrate reduces hepatic steatosis and insulin resistance in HFD-fed mice. Fnofibrate alleviates endoplasmic reticulum stress (ER stress) of mice fed a high fat diet (HFD). Fenofibrate increases the levels of Sarco-endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) which serves as a regulator of ER stress. Further, the levels of let-7 microRNA is also regulated by fenofibrate, and let-7 directly targets 3’-UTR of SERCA2b. Conclusion: The present data suggests that fenofibrate alleviates ER stress through the let-7/SERCA2b axis to protect against excessive lipid accumulation in the liver of Non-alcoholic fatty liver disease (NAFLD) mice.

DEL-1 ameliorates high-fat diet-induced insulin resistance in mouse skeletal muscle through SIRT1/SERCA2-mediated ER stress suppression

2020 ◽  
Vol 171 ◽  
pp. 113730 ◽  
Author(s):  
Jaw Long Sun ◽  
Jinwoo Park ◽  
Taeseung Lee ◽  
Ji Hoon Jeong ◽  
Tae Woo Jung
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Er Stress ◽  
High Fat Diet ◽  
High Fat ◽  
Mouse Skeletal Muscle

scholarly journals Osteocalcin Reverses Endoplasmic Reticulum Stress and Improves Impaired Insulin Sensitivity Secondary to Diet-Induced Obesity Through Nuclear Factor-κB Signaling Pathway

Endocrinology ◽  
2013 ◽  
Vol 154 (3) ◽  
pp. 1055-1068 ◽  
Author(s):  
Bo Zhou ◽  
Huixia Li ◽  
Lin Xu ◽  
Weijin Zang ◽  
Shufang Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Insulin Sensitivity ◽  
Er Stress ◽  
High Fat Diet ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
High Fat ◽  
Impaired Insulin

Abstract Osteocalcin, a synthetic osteoblast-specific protein, has recently emerged as an important regulator of energy metabolism, but the underlying mechanisms are not fully understood. In the present study, mice fed a high-fat diet and receiving osteocalcin showed reduced body weight gain, less fat pad gain, and improved insulin sensitivity as well as increased energy expenditure compared with mice fed a high-fat diet and receiving vehicle. Meanwhile, increased endoplasmic reticulum (ER) stress, defective insulin signaling, and mitochondrial dysfunction induced by obesity were also effectively alleviated by treatment with osteocalcin. Consistent with these findings, the addition of osteocalcin to the culture medium of 3T3-L1 adipocytes, Fao liver cells, and L6 muscle cells markedly reduced ER stress and restored insulin sensitivity. These effects were nullified by blockade of nuclear factor–κB (NF-κB) or phosphatidylinositol 3-kinase but not by U0126, a mitogen-activated protein kinase inhibitor, indicating the causative role of phosphatidylinositol 3-kinase/NF-κB in action of osteocalcin. In addition, the reversal effects of osteocalcin in cells deficient in X-box–binding protein-1, a transcription factor that modulates ER stress response, further confirmed its protective role against ER stress and insulin resistance. Our findings suggest that osteocalcin attenuates ER stress and rescues impaired insulin sensitivity in insulin resistance via the NF-κB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

scholarly journals Successful Versus Failed Adaptation to High-Fat Diet-Induced Insulin Resistance: The Role of IAPP-Induced  -Cell Endoplasmic Reticulum Stress

Diabetes ◽  
2009 ◽  
Vol 58 (4) ◽  
pp. 906-916 ◽  
Author(s):  
A. V. Matveyenko ◽  
T. Gurlo ◽  
M. Daval ◽  
A. E. Butler ◽  
P. C. Butler
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
High Fat Diet ◽  
High Fat
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