scholarly journals Hepatic Knockdown of Endothelin Type A Receptor (ETAR) Ameliorates Hepatic Insulin Resistance and Hyperglycemia Through Suppressing p66Shc-Mediated Mitochondrial Fragmentation in High-Fat Diet-Fed Mice

2021 ◽  
Vol Volume 14 ◽  
pp. 963-981
Author(s):  
Li Feng ◽  
Songhua Wang ◽  
Feng Chen ◽  
Cheng Zhang ◽  
Qiao Wang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Type A ◽  
Hepatic Insulin Resistance ◽  
Mitochondrial Fragmentation ◽  
High Fat ◽  
Endothelin Type A Receptor

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.

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 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.

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 Hepatocyte growth factor alleviates hepatic insulin resistance and lipid accumulation in high-fat diet-fed mice

2018 ◽  
Vol 10 (2) ◽  
pp. 251-260 ◽  
Author(s):  
Yali Jing ◽  
Qingmin Sun ◽  
Xiaolu Xiong ◽  
Ran Meng ◽  
Sunyinyan Tang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Hepatocyte Growth

Ezetimibe decreases SREBP-1c expression in liver and reverses hepatic insulin resistance in mice fed a high-fat diet

Metabolism ◽  
2011 ◽  
Vol 60 (5) ◽  
pp. 617-628 ◽  
Author(s):  
Tomonori Muraoka ◽  
Kazutaka Aoki ◽  
Tomoyuki Iwasaki ◽  
Kazuaki Shinoda ◽  
Akinobu Nakamura ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
High Fat

High fat diet induced hepatic insulin resistance is not related to changes in hypothalamic mRNA expression of NPY, AgRP, POMC and CART in mice

Peptides ◽  
2005 ◽  
Vol 26 (12) ◽  
pp. 2554-2558 ◽  
Author(s):  
A.C. Heijboer ◽  
P.J. Voshol ◽  
E. Donga ◽  
C.G. van Eden ◽  
L.M. Havekes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mrna Expression ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
High Fat

scholarly journals Mice lacking C1q are protected from high fat diet-induced hepatic insulin resistance and impaired glucose homeostasis.

2013 ◽  
Vol 288 (39) ◽  
pp. 28308-28308
Author(s):  
Antoinette D. Hillian ◽  
Megan R. McMullen ◽  
Becky M. Sebastian ◽  
Sanjoy Roychowdhury ◽  
Sangeeta R. Kashyap ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
High Fat

scholarly journals Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor

2014 ◽  
Vol 307 (3) ◽  
pp. E305-E315 ◽  
Author(s):  
Chongben Zhang ◽  
Daniel E. Cooper ◽  
Trisha J. Grevengoed ◽  
Lei O. Li ◽  
Eric L. Klett ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Glycogen Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Lipid Signal ◽  
Mouse Hepatocytes ◽  
Triacylglycerol Accumulation ◽  
Deficient Mice

Glycerol-3-phosphate acyltransferase (GPAT) activity is highly induced in obese individuals with insulin resistance, suggesting a correlation between GPAT function, triacylglycerol accumulation, and insulin resistance. We asked whether microsomal GPAT4, an isoform regulated by insulin, might contribute to the development of hepatic insulin resistance. Compared with control mice fed a high fat diet, Gpat4 −/− mice were more glucose tolerant and were protected from insulin resistance. Overexpression of GPAT4 in mouse hepatocytes impaired insulin-suppressed gluconeogenesis and insulin-stimulated glycogen synthesis. Impaired glucose homeostasis was coupled to inhibited insulin-stimulated phosphorylation of Akt(Ser473) and Akt(Thr308). GPAT4 overexpression inhibited rictor's association with the mammalian target of rapamycin (mTOR), and mTOR complex 2 (mTORC2) activity. Compared with overexpressed GPAT3 in mouse hepatocytes, GPAT4 overexpression increased phosphatidic acid (PA), especially di16:0-PA. Conversely, in Gpat4 −/− hepatocytes, both mTOR/rictor association and mTORC2 activity increased, and the content of PA in Gpat4 −/− hepatocytes was lower than in controls, with the greatest decrease in 16:0-PA species. Compared with controls, liver and skeletal muscle from Gpat4 −/−-deficient mice fed a high-fat diet were more insulin sensitive and had a lower hepatic content of di16:0-PA. Taken together, these data demonstrate that a GPAT4-derived lipid signal, likely di16:0-PA, impairs insulin signaling in mouse liver and contributes to hepatic insulin resistance.

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