Protective Effect of Vanillic Acid against Hyperinsulinemia, Hyperglycemia and Hyperlipidemia via Alleviating Hepatic Insulin Resistance and Inflammation in High-Fat Diet (HFD)-Fed Rats

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.

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

Journal of Ethnopharmacology ◽

10.1016/j.jep.2020.113576 ◽

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

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The Adipose Tissue Endocrine Mechanism of the Prophylactic Protective Effect of Pioglitazone in High-Fat Diet-Induced Insulin Resistance

Journal of International Medical Research ◽

10.1177/147323001204000409 ◽

2012 ◽

Vol 40 (4) ◽

pp. 1304-1316 ◽

Cited By ~ 3

Author(s):

Y Gong ◽

J Li ◽

C Li ◽

Y Mu ◽

Y Xiao ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Protective Effect ◽

High Fat Diet ◽

High Fat ◽

Endocrine Mechanism

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1804379115 ◽

2018 ◽

Vol 115 (38) ◽

pp. E8996-E9005 ◽

Cited By ~ 20

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.

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Kupffer cell activation is a causal factor for hepatic insulin resistance

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00391.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. G107-G116 ◽

Cited By ~ 138

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.

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DHEA protects against visceral obesity and muscle insulin resistance in rats fed a high-fat diet

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.5.r1704 ◽

1997 ◽

Vol 273 (5) ◽

pp. R1704-R1708 ◽

Cited By ~ 20

Author(s):

Polly A. Hansen ◽

Dong Ho Han ◽

Lorraine A. Nolte ◽

May Chen ◽

John O. Holloszy

Keyword(s):

Insulin Resistance ◽

Food Intake ◽

Protective Effect ◽

Fat Mass ◽

Visceral Fat ◽

High Fat Diet ◽

Visceral Obesity ◽

High Fat ◽

Muscle Insulin Resistance

Visceral obesity is frequently associated with muscle insulin resistance. Rats fed a high-fat diet rapidly develop obesity and insulin resistance. Dehydroepiandrosterone (DHEA) has been reported to protect against the development of obesity. This study tested the hypothesis that DHEA protects against the increase in visceral fat and the development of muscle insulin resistance induced by a high-fat diet in rats. Feeding rats a diet providing 50% of the energy as fat for 4 wk resulted in a twofold greater visceral fat mass and a 50% lower rate of maximally insulin-stimulated muscle 2-deoxyglucose (2-DG) uptake compared with controls. Rats fed the high-fat diet plus 0.3% DHEA were largely protected against the increase in visceral fat (+11.3 g in high fat vs. +2.9 g in high fat plus DHEA, compared with controls) and against the decrease in insulin-stimulated muscle 2-DG uptake (0.94 ± 0.15 μmol ⋅ ml−1 ⋅ 20 min−1, controls; 0.46 ± 0.06 μmol ⋅ ml−1 ⋅ 20 min−1, high-fat diet; 0.78 ± 0.07 μmol ⋅ ml−1 ⋅ 20 min−1, high fat + DHEA). DHEA did not affect food intake. These results show that DHEA has a protective effect against accumulation of visceral fat and development of muscle insulin resistance in rats fed a high-fat diet.

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