scholarly journals Diacerhein Improves Glucose Tolerance and Insulin Sensitivity in Mice on a High-Fat Diet

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4080-4093 ◽  
Author(s):  
Natália Tobar ◽  
Alexandre G. Oliveira ◽  
Dioze Guadagnini ◽  
Renata A. Bagarolli ◽  
Guilherme Z. Rocha ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Control Group ◽  
High Fat ◽  
Proinflammatory Mediators

Obesity and type 2 diabetes are characterized by insulin resistance, and the common basis of these events is a chronic and systemic inflammatory process marked by the activation of the c-Jun N-terminal kinase (JNK) and inhibitor-κB kinase (IKKβ)/nuclear factor-κB (NFκB) pathways, up-regulated cytokine synthesis, and endoplasmic reticulum dysfunction. The aim of this study was to evaluate the effects of diacerhein administration, an antiinflammatory drug that reduces the levels of inflammatory cytokines, on insulin sensitivity and signaling in diet-induced obese (DIO) mice. Swiss mice were fed with conventional chow (control group) or a high-fat diet (DIO group). Later, DIO mice were randomly subdivided into a new subgroup (DAR) that received 20 mg/kg diacerhein for 10 d. Western blotting was used to quantify the expression and phosphorylation of insulin receptor, insulin receptor substrate 1, and Akt and of inflammatory mediators that modulate insulin signaling in a negative manner (IKKβ, JNK, and inducible nitric oxide synthase). We show here, for the first time, that the administration of diacerhein in DIO mice improved endoplasmic reticulum stress, reduced JNK and IKKβ phosphorylation, and resulted in a marked improvement in fasting glucose, a decrease in macrophage infiltration in adipose tissue, and a reduced expression and activity of proinflammatory mediators accompanied by an improvement in the insulin signaling mainly in the liver and adipose tissue. Taken together, these results indicate that diacerhein treatment improves insulin sensitivity in obesity, mediated by the reversal of subclinical inflammation, and that this drug may be an alternative therapy for insulin resistance.

scholarly journals Antioxidants preserve redox balance and inhibit c-Jun-N-terminal kinase pathway while improving insulin signaling in fat-fed rats: evidence for the role of oxidative stress on IRS-1 serine phosphorylation and insulin resistance

2008 ◽  
Vol 197 (2) ◽  
pp. 287-296 ◽  
Author(s):  
R Vinayagamoorthi ◽  
Zachariah Bobby ◽  
M G Sridhar
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Redox Balance ◽  
Serine Phosphorylation ◽  
Control Group ◽  
High Fat ◽  
Jnk Pathway

The oxidative stress-sensitive c-Jun-N-terminal kinase (JNK) pathway is known to be activated in diabetic condition and is involved in the progression of insulin resistance. However, the effect of antioxidants on JNK pathway and insulin resistance has not been investigated. The present study was aimed to investigate the effect of antioxidants on redox balance, insulin sensitivity, and JNK pathway in high-fat-fed rats. Male Wistar rats were divided into four groups: the control group – received a rodent chow; control+antioxidant group – fed with rodent chow supplemented with 0.2% (w/w) vitamin E, 0.3% (w/w) vitamin C, and 0.5% (w/w) α-lipoic acid; high-fat group – received high-fat diet; and high fat+antioxidant group – fed with high-fat diet supplemented with above antioxidants. Fat feeding to rats for 9 weeks significantly increased IRS-1 serine phoshorylation, reduced insulin-stimulated IRS-1 tyrosine phosphorylation and insulin sensitivity. High-fat diet also impaired redox balance and activated the redox-sensitive serine kinase – JNK pathway. Antioxidant supplementation along with high-fat diet preserved the free radical defense system, inhibited the activation of JNK pathway, and improved insulin signaling and insulin sensitivity. The present study shows for the first time that antioxidants inhibit JNK pathway and IRS-1 serine phosphorylation while improving insulin sensitivity in fat-fed rats. These findings implicate the beneficial effect of antioxidants in obesity-/dyslipidemia-induced insulin resistance in humans.

scholarly journals Resveratrol reduces the inflammatory response in adipose tissue and improves adipose insulin signaling in high-fat diet-fed mice

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5173 ◽  
Author(s):  
Shibin Ding ◽  
Jinjin Jiang ◽  
Zhe Wang ◽  
Guofu Zhang ◽  
Jianli Yin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Inflammatory Response ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Density Lipoprotein ◽  
High Fat

Background Obesity-induced glucose metabolism disorder is associated with chronic, low-grade, systemic inflammation and is considered a risk factor for diabetes and metabolic syndrome. Resveratrol (RES), a natural anti-inflammatory compound, is observed to improve glucose tolerance and insulin sensitivity in obese rodents and humans. This study aimed to test the effects of RES administration on insulin signaling and the inflammatory response in visceral white adipose tissue (WAT) caused by a high-fat diet (HFD) in mice. Methods A total of 40 wild-type C57BL/6 male mice were divided into four groups (10 in each group): the standard chow diet (STD) group was fed a STD; the HFD group was fed a HFD; and the HFD-RES/L and HFD-RES/H groups were fed a HFD plus RES (200 and 400 mg/kg/day, respectively). The L and H in RES/L and RES/H stand for low and high, respectively. Glucose tolerance, insulin sensitivity, circulating inflammatory biomarkers and lipid profile were determined. Quantitative PCR and Western blot were used to determine the expression of CC-chemokine receptor 2 (CCR2), other inflammation markers, glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS-1) and pAkt/Akt and to assess targets of interest involving glucose metabolism and inflammation in visceral WAT. Results HFD increased the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and proinflammatory cytokines in serum, decreased the high-density lipoprotein cholesterol level in serum, and induced insulin resistance and WAT inflammation in mice. However, RES treatment alleviated insulin resistance, increased the expressions of pAkt, GLUT4 and IRS-1 in WAT, and decreased serum proinflammatory cytokine levels, macrophage infiltration and CCR2 expression in WAT. Conclusion Our results indicated that WAT CCR2 may play a vital role in macrophage infiltration and the inflammatory response during the development of insulin resistance in HFD-induced obesity. These data suggested that administration of RES offers protection against abnormal glucose metabolism and inflammatory adaptations in visceral WAT in mice with HFD-induced obesity.

scholarly journals Oleacein Prevents High Fat Diet-Induced A Diposity and Ameliorates Some Biochemical Parameters of Insulin Sensitivity in Mice

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1829 ◽  
Author(s):  
Lepore ◽  
Maggisano ◽  
Bulotta ◽  
Mignogna ◽  
Arcidiacono ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Fatty Acid Synthase ◽  
Glucose Transporter ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
High Fat

Oleacein is one of the most abundant polyphenolic compounds of olive oil, which has been shown to play a protective role against several metabolic abnormalities, including dyslipidemia, insulin resistance, and glucose intolerance. Herein, we investigated the effects of oleacein on certain markers of adipogenesis and insulin-resistance in vitro, in 3T3-L1 adipocytes, and in vivo in high-fat diet (HFD)-fed mice. During the differentiation process of 3T3-L1 preadipocytes into adipocytes, oleacein strongly inhibited lipid accumulation, and decreased protein levels of peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid synthase (FAS), while increasing Adiponectin levels. In vivo, treatment with oleacein of C57BL/6JOlaHsd mice fed with HFD for 5 and 13 weeks prevented the increase in adipocyte size and reduced the inflammatory infiltration of macrophages and lymphocytes in adipose tissue. These effects were accompanied by changes in the expression of adipose tissue-specific regulatory elements such as PPARγ, FAS, sterol regulatory element-binding transcription factor-1 (SREBP-1), and Adiponectin, while the expression of insulin-sensitive muscle/fat glucose transporter Glut-4 was restored in HFD-fed mice treated with oleacein. Collectively, our findings indicate that protection against HFD-induced adiposity by oleacein in mice is mediated by the modulation of regulators of adipogenesis. Protection against HFD-induced obesity is effective in improving peripheral insulin sensitivity.

scholarly journals Electroacupuncture Mitigates Skeletal Muscular Lipid Metabolism Disorder Related to High-Fat-Diet Induced Insulin Resistance through the AMPK/ACC Signaling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Zhixing Li ◽  
Danchun Lan ◽  
Haihua Zhang ◽  
Hongtao Zhang ◽  
Xiaozhuan Chen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Control Group ◽  
Sensitivity Index ◽  
Model Assessment ◽  
Sprague Dawley ◽  
High Fat ◽  
Lipid Metabolism Disorder ◽  
Metabolism Disorder

The aim of this work is to investigate the effect of electroacupuncture (EA) on insulin sensitivity in high-fat diet (HFD) induced insulin resistance (IR) rats and to evaluate expression of AMPK/ACC signaling components. Thirty-two male Sprague-Dawley rats were randomized into control group, HFD group, HFD+Pi (oral gavage of pioglitazone) group, and HFD+EA group. Acupuncture was subcutaneously applied to Zusanli (ST40) and Sanyinjiao (SP6). For Zusanli (ST40) and Sanyinjiao (SP6), needles were connected to an electroacupuncture (EA) apparatus. Fasting plasma glucose was measured by glucose oxidase method. Plasma fasting insulin (FINS) and adiponectin (ADP) were determined by ELISA. Triglyceride (TG) and cholesterol (TC) were determined by Gpo-pap. Proteins of adiponectin receptor 1 (adipoR1), AMP-activated Protein Kinase (AMPK), and acetyl-CoA carboxylase (ACC) were determined by Western blot, respectively. Compared with the control group, HFD group exhibits increased levels of FPG, FINS, and homeostatic model assessment of insulin resistance (HOMA-IR) and decreased level of ADP and insulin sensitivity index (ISI). These changes were reversed by both EA and pioglitazone. Proteins of adipoR1 and AMPK were decreased, while ACC were increased in HFD group compared to control group. Proteins of these molecules were restored back to normal levels upon EA and pioglitazone. EA can improve the insulin sensitivity of insulin resistance rats; the positive regulation of the AMPK/ACC pathway in the skeletal muscle may be a possible mechanism of EA in the treatment of IR.

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

2016 ◽  
Vol 242 (4) ◽  
pp. 441-447 ◽  
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.

Beta-sitosterol attenuates insulin resistance in adipose tissue via IRS-1/Akt mediated insulin signaling in high fat diet and sucrose induced type-2 diabetic rats

2020 ◽  
Vol 873 ◽  
pp. 173004 ◽  
Author(s):  
Shyamaladevi Babu ◽  
Madhan Krishnan ◽  
Ponnulakshmi Rajagopal ◽  
Vijayalakshmi Periyasamy ◽  
Vishnupriya Veeraraghavan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Diabetic Rats ◽  
High Fat ◽  
Type 2 Diabetic

scholarly journals Metabolic consequences of ENPP1 overexpression in adipose tissue

2011 ◽  
Vol 301 (5) ◽  
pp. E901-E911 ◽  
Author(s):  
Wentong Pan ◽  
Ester Ciociola ◽  
Manish Saraf ◽  
Batbayar Tumurbaatar ◽  
Demidmaa Tuvdendorj ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Fatty Liver ◽  
Insulin Receptor ◽  
High Fat Diet ◽  
Tolerance Test ◽  
Chow Diet ◽  
High Fat ◽  
The Metabolic Syndrome ◽  
Feeding Protocol

Ectonucleotide pyrophosphate phosphodiesterase (ENPP1) has been shown to negatively modulate insulin receptor and to induce cellular insulin resistance when overexpressed in various cell types. Systemic insulin resistance has also been observed when ENPP1 is overexpressed in multiple tissues of transgenic models and attributed largely to tissue insulin resistance induced in skeletal muscle and liver. Another key tissue in regulating glucose and lipid metabolism is adipose tissue (AT). Interestingly, obese patients with insulin resistance have been reported to have increased AT ENPP1 expression. However, the specific effects of ENPP1 in AT have not been studied. To better understand the specific role of AT ENPP1 on systemic metabolism, we have created a transgenic mouse model (C57/Bl6 background) with targeted overexpression of human ENPP1 in adipocytes, using aP2 promoter in the transgene construct ( AdiposeENPP1-TG). Using either regular chow or pair-feeding protocol with 60% fat diet, we compared body fat content and distribution and insulin signaling in adipose, muscle, and liver tissues of AdiposeENPP1-TG and wild-type (WT) siblings. We also compared response to intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT). Our results show no changes in Adipose ENPP1-TG mice fed a regular chow diet. After high-fat diet with pair-feeding protocol, AdiposeENPP1-TG and WT mice had similar weights. However, AdiposeENPP1-TG mice developed fatty liver in association with changes in AT characterized by smaller adipocyte size and decreased phosphorylation of insulin receptor Tyr1361 and Akt Ser473. These changes in AT function and fat distribution were associated with systemic abnormalities of lipid and glucose metabolism, including increased plasma concentrations of fatty acid, triglyceride, plasma glucose, and insulin during IPGTT and decreased glucose suppression during ITT. Thus, our results show that, in the presence of a high-fat diet, ENPP1 overexpression in adipocytes induces fatty liver, hyperlipidemia, and dysglycemia, thus recapitulating key manifestations of the metabolic syndrome.

Long-term melatonin administration improves glucose homeostasis and insulin resistance state in high-fat-diet fed rats

2013 ◽  
Vol 8 (10) ◽  
pp. 958-967
Author(s):  
Xue-Dong Wan ◽  
San-Qiang Li ◽  
Shou-Min Xi ◽  
Jian-Fei Wang ◽  
Yan-Chun Guo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Metabolic Profiles ◽  
Oxygen Species ◽  
High Fat

AbstractEmerging evidence support an important role of reactive oxygen species in various forms of insulin resistance. It is identified that melatonin has antioxidant properties and prevents toxic effects of reactive oxygen species. In this study, we sought to assess the involvement of melatonin in the progression of insulin resistance in response to a high-fat diet (HFD) and to investigate the underlying mechanisms. Male rats were fed with a control diet, a high-fat diet, or a high-fat diet supplemented with melatonin (5 mg kg−1, i.p.) for 10 weeks. Glucose homeostasis, insulin sensitivity, antioxidative potency, and metabolic profiles in the rats were evaluated. Our results showed that a HFD led to increasing body mass, adipose tissue weight, plasma insulin, total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), and decreased HDL-cholesterol (HDL-C) in rats. There was also a significant increase in the level of malondialdehyde (MDA) and decrease in superoxide dismutase (SOD) activity, oxidative stress markers both in the plasma and liver. An enhanced hepatic phosphoenolpyruvate carboxy-kinase (PEPCK) activity and RNA expression were observed. Impaired insulin signaling was evidenced by reducing insulin receptor substrate 2 (IRS2) tyrosine phosphorylation and protein kinase B (PKB) serine phosphorylation in response to insulin. Overactivation of stress-activated protein kinases JNK was also observed in the liver of HFD rats. However, simultaneous administration of melatonin to HFD rats significantly reduced oxidative stress in the system and liver, markedly improved impaired glucose homeostasis, insulin sensitivity, antioxidative potency, metabolic profiles and all the aforesaid adverse changes in HFD rats. Our results demonstrated that anti-oxidative property of melatonin is sufficient to ameliorate the insulin resistance condition, leading to the improvement of glucose homeostasis and the restoration of hepatic insulin signaling in a rat model of HFD-induced insulin resistance.

Abstract 213: Phospholipid Transfer Protein Deficiency Attenuates High-Fat Diet--Induced Obesity and Insulin Resistance

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Guohua Song ◽  
Chuanlong Zong ◽  
Mingzhu Shao ◽  
Yang Yu ◽  
Shoudong Guo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Receptor ◽  
High Fat Diet ◽  
Phospholipid Transfer Protein ◽  
Insulin Stimulation ◽  
High Fat ◽  
Transfer Protein ◽  
Diet Induced Obesity ◽  
Phospholipid Transfer

Increased phospholipid transfer protein (PLTP) activity has been found to be associated with diabetes, obesity, and metabolic syndrome in humans. However, whether or not PLTP has a direct effect on insulin sensitivity and obesity is largely unknown. Here we analyzed the effect by using PLTP knockout (PLTP-/-) mouse model. Although, PLTP-/- mice have normal body-weight-gain under chow diet, these mice were protected from high-fat-diet-induced obesity and insulin resistance, compared with wild type mice. In order to understand the mechanism, we evaluated insulin receptor and Akt activation and found that PLTP deficiency significantly enhanced phosphorylated insulin receptor and Akt levels in high-fat-diet fed mouse livers, adipose tissues, and muscles after insulin stimulation, while total Akt and insulin receptor levels were unchanged. Moreover we found that the deficiency induced significantly more GLUT4 immunostaining in the plasma membranes of adipocytes and muscle cells after insulin stimulation. Finally, we found that PLTP deficient hepatocytes had less sphingomyelin and free cholesterol in the plasma membrane and lipid raft than that of controls and this may provide a molecular basis for PLTP deficiency-mediated increasing in insulin sensitivity. We have concluded that PLTP deficiency leads to an improvement in tissue and whole-body insulin sensitivity in high-fat-diet induced insulin resistance mice model. Foundation:National Natural Science Foundation of China (# 81070247, 81170785) and Taishan Scholar Foundation of Shandong Province.

scholarly journals Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates Diet-induced Endoplasmic Reticulum Stress in Liver and Adipose Tissue

2013 ◽  
Vol 288 (20) ◽  
pp. 14189-14199 ◽  
Author(s):  
Ahmed Bettaieb ◽  
Naoto Nagata ◽  
Daniel AbouBechara ◽  
Samah Chahed ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Er Stress ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Hepg2 Cells ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
High Fat ◽  
Pharmacological Inhibition

Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has beneficial effects in cardiovascular, inflammatory, and metabolic diseases in murine models. Mice with targeted deletion or pharmacological inhibition of sEH exhibit improved insulin signaling in liver and adipose tissue. Herein, we assessed the role of sEH in regulating endoplasmic reticulum (ER) stress in liver and adipose tissue. We report that sEH expression was increased in the livers and adipose tissue of mice fed a high fat diet, the adipose tissue of overweight humans, and palmitate-treated cells. Importantly, sEH deficiency or inhibition in mice attenuated chronic high fat diet-induced ER stress in liver and adipose tissue. Similarly, pharmacological inhibition of sEH in HepG2 cells and 3T3-L1 adipocytes mitigated chemical-induced ER stress and activation of JNK, p38, and cell death. In addition, insulin signaling was enhanced in HepG2 cells treated with sEH substrates and attenuated in cells treated with sEH products. In summary, these findings demonstrate that sEH is a physiological modulator of ER stress and a potential target for mitigating complications associated with obesity.

Sign in / Sign up

Export Citation Format

Share Document