scholarly journals PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling

2018 ◽  
Vol 115 (38) ◽  
pp. E8996-E9005 ◽  
Author(s):  
Brandon M. Gassaway ◽  
Max C. Petersen ◽  
Yulia V. Surovtseva ◽  
Karl W. Barber ◽  
Joshua B. Sheetz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Phosphorylation ◽  
Cross Talk ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Large Scale ◽  
Kinase Assay ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
The Impact

Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat–fed, and high-fat–fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.

Ethno-pharmacological insulin signaling induction of aqueous extract of Syzygium paniculatum fruits in a high-fat diet induced hepatic insulin resistance

2020 ◽  
pp. 113576
Author(s):  
Prabhakar Yellanur Konda ◽  
Vidyasagar Chennupati ◽  
Sreenivasulu Dasari ◽  
Nishesh Sharma ◽  
Muthukumaran Muthulingam ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Aqueous Extract ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
High Fat

scholarly journals Effect of BI-1 on insulin resistance through regulation of CYP2E1

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Geum-Hwa Lee ◽  
Kyoung-Jin Oh ◽  
Hyung-Ryong Kim ◽  
Hye-Sook Han ◽  
Hwa-Young Lee ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Er Stress ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Stable Expression ◽  
Hepatic Insulin Resistance ◽  
Ros Production ◽  
High Fat ◽  
Knock Out ◽  
Knock Out Mice

Abstract Diet-induced obesity is a major contributing factor to the progression of hepatic insulin resistance. Increased free fatty acids in liver enhances endoplasmic reticulum (ER) stress and production of reactive oxygen species (ROS), both are directly responsible for dysregulation of hepatic insulin signaling. BI-1, a recently studied ER stress regulator, was examined to investigate its association with ER stress and ROS in insulin resistance models. To induce obesity and insulin resistance, BI-1 wild type and BI-1 knock-out mice were fed a high-fat diet for 8 weeks. The BI-1 knock-out mice had hyperglycemia, was associated with impaired glucose and insulin tolerance under high-fat diet conditions. Increased activity of NADPH-dependent CYP reductase-associated cytochrome p450 2E1 (CYP2E1) and exacerbation of ER stress in the livers of BI-1 knock-out mice was also observed. Conversely, stable expression of BI-1 in HepG2 hepatocytes was shown to reduce palmitate-induced ER stress and CYP2E1-dependent ROS production, resulting in the preservation of intact insulin signaling. Stable expression of CYP2E1 led to increased ROS production and dysregulation of insulin signaling in hepatic cells, mimicking palmitate-mediated hepatic insulin resistance. We propose that BI-1 protects against obesity-induced hepatic insulin resistance by regulating CYP2E1 activity and ROS production.

scholarly journals CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice

2020 ◽  
Vol 244 (2) ◽  
pp. 353-367 ◽  
Author(s):  
Jiali Liu ◽  
Yue Li ◽  
Xiaoyan Zhou ◽  
Xi Zhang ◽  
Hao Meng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Inflammatory Response ◽  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Insulin Action ◽  
Hepatic Insulin Resistance ◽  
Obese Mice ◽  
High Fat ◽  
Impaired Insulin

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

Kupffer cell activation is a causal factor for hepatic insulin resistance

2010 ◽  
Vol 298 (1) ◽  
pp. G107-G116 ◽  
Author(s):  
Nicolas Lanthier ◽  
Olivier Molendi-Coste ◽  
Yves Horsmans ◽  
Nico van Rooijen ◽  
Patrice D. Cani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Kupffer Cell ◽  
High Fat Diet ◽  
Cell Activation ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Short Term ◽  
Adipose Tissue Macrophages ◽  
Diet Model

Recruited adipose tissue macrophages contribute to chronic and low-grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high-fat diet. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by Western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high-fat diet. Here, we characterized a short-term high-fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short-term high-fat diet model. Our study clearly shows that hepatic macrophage response participates to the onset of high-fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet- and obesity-induced insulin resistance.

scholarly journals Effects of Distinct n-6 to n-3 Polyunsaturated Fatty Acid Rations on Insulin Resistant and AD-like Phenotypes in High-Fat Diets-Fed APP/PS1 Transgenic Mice

2021 ◽  
Author(s):  
Xiaojun Ma ◽  
Yujie Guo ◽  
Pengfei Li ◽  
Jingjing Xu ◽  
Shengqi Dong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
High Fat ◽  
Pufa Ratio ◽  
Pro Inflammatory Cytokines

Abstract Background: Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Polyunsaturated fatty acids (PUFAs) are essential in maintaining normal brain function. However, little is known about the impact of dietary n-6/n-3 PUFA ratio on AD-like pathology, especially in high-fat diet (HFD)-fed AD model mice. Methods: In the present study, the APP/PS1 mice were treated with 60% HFD for 3.5 months to induced insulin resistance. After that, 45% HFD with different n-6/n-3 PUFA ratios (n-6/n-3=1:1, 5:1 or 16:1) was applied for additional 3.5 months treatment. Following the dietary intervention, the behavior of mice was observed using the Water maze. Following behavioral testing, the animals were euthanized, and serum and tissue samples were collected for biochemical, histological and pathological analyses and evaluation. Cortical fatty acid profile was measured by gas chromatography. Western Blot and immunohistochemistry methods were used to detect protein expression of molecules related to AD pathology and insulin signaling pathway(s) in the brain sample tissues. Immunofluorescence assay was used to uncover the expression and migration of NF-κB in the cortex. qPCR method was applied to determine the gene expression of cortical pro-inflammatory cytokines.Results: HFD caused insulin resistance, increased serum IL-6 and TNF-α level, elevated cortical soluble Aβ1-40, Aβ1-42 content, and increased brain n-6/n-3 PUFAs ratio in APP/PS1 mice. Increased APP and BACE1 protein expression and p-IR/IR ratio, but decreased pro-inflammatory cytokines mRNA expression was observed in the cortex from 60% HFD-fed APP/PS1 mice. N-3 PUFAs rich diet (n-6/n-3=1:1) relieved insulin resistance and hyperlipidemia induced by 60% HFD. Cortical soluble Aβ1-40 and Aβ1-42 contents, the expression of cortical APP, GLUT3, insulin metabolism related molecules, and NF-κB pathway downstream pro-inflammatory cytokines showed a dietary n-6/n-3 PUFAs ratio-dependent way, indicating that dietary n-6/n-3 PUFA ratio plays a critical role in modifying the responses of serum inflammatory cytokine, AD pathology, cortical n-6/n-3 PUFAs ratio, insulin signaling and neuroinflammation to HFD treatment.Conclusion: Dietary n-6/n-3 PUFA ratio play an important role in modifying AD pathophysiology, insulin signaling pathway, and neuro-inflammation response to high fat diet treatment in brain.

scholarly journals Exercise Alleviates Cognitive Functions by Enhancing Hippocampal Insulin Signaling and Neuroplasticity in High-Fat Diet-Induced Obesity

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1603 ◽  
Author(s):  
Hye-Sang Park ◽  
Sang-Seo Park ◽  
Chang-Ju Kim ◽  
Mal-Soon Shin ◽  
Tae-Woon Kim
Keyword(s):  
Insulin Resistance ◽  
Cognitive Function ◽  
Physical Exercise ◽  
Dentate Gyrus ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Treadmill Exercise ◽  
High Fat ◽  
Brain Functions ◽  
Impaired Cognitive Function

Obesity, caused by a high-fat diet (HFD), leads to insulin resistance, which is a precursor of diabetes and a risk factor for impaired cognitive function, dementia, and brain diseases, such as Alzheimer’s disease. Physical exercise has positive effects on obesity and brain functions. We investigated whether the decline in cognitive function caused by a HFD could be improved through exercise by examining insulin signaling pathways and neuroplasticity in the hippocampus. Four-week-old C57BL/6 male mice were fed a HFD or a regular diet for 20 weeks, followed by 12 weeks of treadmill exercise. To ascertain the effects of treadmill exercise on impaired cognitive function caused by obesity, the present study implemented behavioral testing (Morris water maze, step-down). Moreover, insulin-signaling and neuroplasticity were measured in the hippocampus and dentate gyrus. Our results demonstrated that HFD-fed obesity-induced insulin resistance was improved by exercise. In addition, the HFD group showed a decrease in insulin signaling and neuroplasticity in the hippocampus and the dentate gyrus and increased cognitive function impairment, which were reversed by physical exercise. Overall, our findings indicate that physical exercise may act as a non-pharmacologic method that protects against cognitive dysfunction caused by obesity by improving hippocampal insulin signaling and neuroplasticity.

Effect of synbiotic supplementation on asprosin level in high fat diet-induced metabolic disorder in pregnant rats

2021 ◽  
pp. 1-10
Author(s):  
Mehrdad Naghizadeh ◽  
Mansour Karajibani ◽  
Hamed Fanaei ◽  
Farzaneh Montazerifar ◽  
Alireza Dashipour
Keyword(s):  
Insulin Resistance ◽  
Birth Weight ◽  
Lipid Profile ◽  
Total Cholesterol ◽  
High Fat Diet ◽  
Density Lipoprotein ◽  
High Fat ◽  
Pregnant Rats ◽  
Synbiotic Supplementation ◽  
The Impact

Synbiotic supplementation can improve metabolic disorders. The aim of this study was to assess the impact of synbiotic supplementation on the levels of asprosin, lipid profile, glucose, and insulin resistance in pregnant rats fed a high-fat diet (HFD). Rats were divided into three groups: control group (fed base chow), HFD group, and HFD + synbiotic group. Levels of blood glucose, total cholesterol, triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), insulin, and asprosin levels were measured. Birth weight of offspring in the HFD + synbiotic group was significantly lower than in the HFD group. Similarly, serum asprosin, insulin, insulin resistance, TG and total cholesterol levels in the HFD + symbiotic group were significantly lower than in the HFD group. Asprosin levels had a significant and positive correlation between food intake in the first ten days of the experiment and gestation period, fasting blood sugar (FBS), TG, and homeostatic model assessment (HOMA) index. Moreover, asprosin levels had a significant and negative correlation with HDL and insulin levels. Results showed, synbiotic supplementation has beneficial effects on obese animals and improves weight gain during pregnancy, pup birth weight, FBS, insulin resistance and lipid profile. These advantages of synbiotic supplementation could be mediated by reducing serum asprosin levels.

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.

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