Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice

Background/Aims: Sepsis is a common disease that continues to increase in prevalence worldwide, and diabetes mellitus may make the situation worse. This study was designed to determine the role of Liver Kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in diabetic mice complicated with systemic endotoxemia. Methods: The effects of LKB1/AMPK signaling pathway activation on endotoxemia were investigated in streptozotocin induced diabetic mice (STZ-mice) and db/db diabetic mice. Primary peritoneal macrophages and human umbilical vein endothelial cells (HUVECs) monolayers were simultaneously stimulated by both high glucose and LPS and used as a model to investigate the potential molecular mechanisms in vitro. Results: After treatment with LPS, high glucose or both LPS and high glucose, phosphor-AMPK expression was decreased, and moreover, AMPK activation by metformin treatment alleviated the decrease in phosphor-AMPK expression in HUVECs and macrophages as well as in lung tissue. Furthermore, both LPS and high glucose co-treatment decreased LKB1 and phosphor-AMPK expression via enhanced oxidative stress response, and importantly, LKB1 overexpression mediated by adenovirus inhibited the decrease in phosphor-AMPK expression in macrophages and HUVECs. AMPK activation by metformin administration improved the survival of STZ-induced diabetic mice and db/db diabetic mice, which was associated with reduced lung endothelial hyperpermeability and systemic inflammatory response. Furthermore, the permeability of HUVECs monolayers induced by both high glucose and LPS stimulation was also alleviated by AMPK activation, which was partly via suppression of VE-cadherin phosphorylation. Conclusion: These data demonstrated that LKB1/AMPK signaling pathway activation improved the survival of diabetic mice complicated with endotoxemia. Thus, LKB1/AMPK signaling pathway may serve as a potentially useful therapeutic target for severe infection in diabetic patients.

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Delphinidin-induced autophagy protects pancreatic β cells against apoptosis resulting from high-glucose stress via AMPK signaling pathway

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmz126 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1242-1249 ◽

Cited By ~ 5

Author(s):

Dengni Lai ◽

Mingyong Huang ◽

Lingyan Zhao ◽

Yan Tian ◽

Yong Li ◽

...

Keyword(s):

Signaling Pathway ◽

High Glucose ◽

Cell Mass ◽

Protective Role ◽

Common Disease ◽

Β Cells ◽

Pancreatic Β Cells ◽

Ampk Signaling ◽

Compound C ◽

Induced Apoptosis

Abstract Hyperglycemia, a diagnostic characteristic of diabetes mellitus, is detrimental to pancreatic β cells. Delphinidin, a member of the anthocyanin family, inhibits glucose absorption, increases glucagon-like peptide-1 (GLP-1) secretion, and improves insulin secretion in diabetes. However, whether delphinidin plays a protective role in pancreatic β-cell mass and function is not clear. In this study, delphinidin was found to decrease the high-glucose-induced apoptosis of RIN-m5F pancreatic β cells. In addition, delphinidin induced autophagy in RIN-m5F cells under the normal and high-glucose conditions, while 3-methyladenine (3-MA) inhibition of autophagy significantly diminished the protective role of delphinidin against high-glucose-induced apoptosis of pancreatic β cells. Delphinidin also decreased the level of cleaved caspase 3 and increased the phosphorylation level of AMP-activated protein kinase α (AMPKα) Thr172. Compound C, an AMPK inhibitor, was found to decrease the ratio of LC3-II/LC3-I, and the apoptotic rate of high-glucose-injured cells was increased after treatment with delphinidin, indicating that delphinidin attenuated the negative effects of high-glucose stress to cells. In conclusion, our data demonstrate that delphinidin protects pancreatic β cells against high-glucose-induced injury by autophagy regulation via the AMPK signaling pathway. These findings might shed light on the underlying mechanisms of diabetes and help improve the prevention and therapy of this common disease.

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Effects of dietary corticosterone on the central adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in broiler chickens

Journal of Animal Science ◽

10.1093/jas/skaa202 ◽

2020 ◽

Vol 98 (7) ◽

Author(s):

Xiyi Hu ◽

Yuanli Cai ◽

Linglian Kong ◽

Hai Lin ◽

Zhigang Song ◽

...

Keyword(s):

Protein Kinase ◽

Signaling Pathway ◽

Broiler Chickens ◽

Fatty Acid Synthase ◽

Average Daily Gain ◽

Mammalian Target Of Rapamycin ◽

Adenosine Monophosphate ◽

Ampk Signaling ◽

Protein Levels ◽

Liver Kinase B1

Abstract Glucocorticoids (GCs) induce the activation of the central adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling pathway in birds. In this study, we aimed to investigate the effects of corticosterone (CORT) supplemented in diet on the central AMPK signaling pathway in broilers. The average daily gain was reduced by CORT treatment, and the average daily feed intake remained unchanged. Plasma glucose, triglyceride, total cholesterol, and CORT contents were increased by CORT administration. In addition, CORT treatment decreased the relative weights of heart, spleen, and bursa and increased the relative weights of liver and abdominal fat. The glycogen contents in the liver and breast muscle were higher in the chicks treated with CORT. CORT treatment upregulated the gene expression of mammalian target of rapamycin, glucocorticoid receptor, AMPKα2, neuropeptide Y(NPY), liver kinase B1 (LKB1), AMPKα1, and fatty acid synthase in the hypothalamus. Moreover, CORT treatment increased the protein levels of acetyl-coenzyme A carboxylase (ACC) phosphorylation and total AMPK and phosphorylated AMPK in the hypothalamus. Hence, CORT administration in the diet activated the LKB1-AMPK-NPY/ACC signaling pathway in the hypothalamus of broiler.

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Abstract 12099: Activated Notch1 Interacting With LKB1 Reduces Myocardial Ischemic Injury via Modulating AMPK Signaling Pathway

Circulation ◽

10.1161/circ.130.suppl_2.12099 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Hui Yang ◽

Wanqing Sun ◽

Yina Ma ◽

Xingchi Chen ◽

George Techiryan ◽

...

Keyword(s):

Myocardial Infarction ◽

Protein Kinase ◽

Myocardial Ischemia ◽

Signaling Pathway ◽

Ischemic Heart ◽

Signaling Cascade ◽

Ampk Activation ◽

Ampk Signaling ◽

Notch1 Signaling

Introduction: The activation of the intrinsic AMP-activated protein kinase (AMPK) pathway plays an important role in the myocardial response to ischemia, pressure overload, and heart failure. The Notch1 signaling in the adult myocardium is activated transiently in response to myocardial injury, and it has implicated that Notch1 signaling may contribute to cardiac repair. However, the role of Notch1 signaling in myocardial infarction remain uncertain. Hypothesis: The cardioprotective AMPK signaling pathway could mediate the beneficial effects of Notch1 signaling cascade during myocardial infarction. Methods: C57BL/6J male mouse hearts were subjected in vivo to left anterior descending coronary artery ligation for 5 min, 20 min, 24 hr, 1 week and 2 weeks. Mice were treated with dibenzazepine (DBZ), a new Notch γ-secretase inhibitor (5 μmol/kg/day, i.p.) and the vehicle groups were treated with saline. Ischemic heart tissues were harvested for protein, mRNA expression and histologic analysis. Results: The Notch1 signaling was significantly activated during myocardial ischemia in vivo (p<0.05 vs. sham group). Interestingly, in the ex vivo heart perfusion system, systemic administration of DBZ to hearts led to significantly increase of myocardial infarct size and apoptosis caused by myocardial ischemia (p<0.05 vs. vehicle group). The immunoblotting results demonstrated that DBZ treatment significantly inhibited the AMPK activation by myocardial ischemia (p<0.05 vs. ischemia alone). Further immunoprecipitation experimental data showed that activated Notch1 strongly interacts with one AMPK upstream kinase, LKB1, to form a complex that modulates cardiac AMPK activation during myocardial ischemia. Moreover, the inhibition of Notch1 by DBZ impaired AMPK activation that significantly increased inflammation response such as activation of c-Jun N-terminal protein kinase (JNK) and NF-κB signaling during myocardial ischemia. Conclusions: The activated Notch1 signaling interacts with LKB1 to trigger the activation of cardioprotective AMPK signaling during myocardial ischemia. The Notch1-LKB1-AMPK signaling cascade could be a potential pharmacologic mimic for cardioprotection of ischemic heart disease.

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ERM Complex, a Therapeutic Target for Vascular Leakage Induced by Diabetes

Current Medicinal Chemistry ◽

10.2174/0929867328666210526114417 ◽

2021 ◽

Vol 28 ◽

Author(s):

Olga Simó-Servat ◽

Hugo Ramos ◽

Patricia Bogdanov ◽

Marta García-Ramírez ◽

Jordi Huerta ◽

...

Keyword(s):

High Glucose ◽

Therapeutic Target ◽

Vascular Leakage ◽

Cell Permeability ◽

Diabetic Patients ◽

Diabetic Mice ◽

Erm Proteins ◽

High Glucose Condition ◽

Tnf Α ◽

Glucose Condition

Background: Ezrin, radixin, and moesin (the ERM complex) interact directly with membrane proteins regulating their attachment to actin filaments. ERM protein activation modifies cytoskeleton organization and alters the endothelial barrier function, thus favoring vascular leakage. However, little is known regarding the role of ERM proteins in diabetic retinopathy (DR). Objective: This study aimed to examine whether overexpression of the ERM complex exists in db/db mice and its main regulating factors. Methods: 9 male db/db mice and 9 male db/+ aged 14 weeks were analyzed. ERM proteins were assessed by western blot and by immunohistochemistry. Vascular leakage was determined by the Evans blue method. To assess ERM regulation, HRECs were cultured in a medium containing 5.5 mM D-glucose (mimicking physiological conditions) and 25 mM D-glucose (mimicking hyperglycemia that occurs in diabetic patients). Moreover, treatment with TNF-α, IL-1β, or VEGF was added to a high glucose condition. The expression of ERM proteins was quantified by RT-PCR. Cell permeability was evaluated by measuring movements of FITC-dextran. Results: A significant increase of ERM in diabetic mice in comparison with non-diabetic mice was observed. A high glucose condition alone did not have any effect on ERM expression. However, TNF-α and IL-1β induced a significant increase in ERM proteins. Conclusion: The increase of ERM proteins induced by diabetes could be one of the mechanisms involved in vascular leakage and could be considered as a therapeutic target. Moreover, the upregulation of the ERM complex by diabetes is induced by inflammatory mediators rather than by high glucose itself.

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Abstract 26: Fibroblast Growth Factor 21 Prevents Diabetic Cardiomyopathy by Attenuating Cardiac Lipotoxicity via Erk1/2-dependent Signaling Pathway in Mice

Circulation Research ◽

10.1161/res.117.suppl_1.26 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Yi Tan ◽

Chi Zhang ◽

Xiaoqing Yan ◽

Zhifeng Huang ◽

Junlian Gu ◽

...

Keyword(s):

Cell Death ◽

Type 1 Diabetes ◽

Signaling Pathway ◽

P38 Mapk ◽

Diabetic Cardiomyopathy ◽

Cardiac Cell ◽

Diabetic Mice ◽

Ampk Signaling

The role of FGF21 plays in the development and progression of diabetic cardiomyopathy (DCM) has not been addressed. Here we demonstrated that type 1 diabetes decreased FGF21 levels in the blood, but up-regulated cardiac fgf21 expression about 40 fold at 2 months and 3-1.5 fold at 4 and 6 months after diabetes, which indicated a cardiac specific FGF21 adaptive up-regulation. To define the critical role of FGF21 in DCM, type 1 diabetes was induced in FGF21 knock out (FGF21KO) mice. At 1, 2 and 4 months after diabetes onset, no significant differences between FGF21KO and wild type (WT) diabetic mice in blood glucose and triglyceride levels were observed. But FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodeling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Mechanistically, FGF21 reduced palmitate-induced cardiac cell death, which was accompanied by up-regulation of cardiac Erk1/2, p38 MAPK and AMPK phosphorylation. Inhibition of each kinase with its inhibitor and/ or siRNA revealed that FGF21 prevents palmitate-induced cardiac cell death via up-regulating the Erk1/2-dependent p38 MAPK/AMPK signaling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic mice significantly prevented cardiac cell death and reduced inactivation of Erk1/2, p38 MAPK and AMPK, and prevented cardiac remodeling and dysfunction at late-stage. Our results demonstrate that cardiac FGF21 decompensation may contribute to the development of DCM and FGF21 may be a therapeutic target for the treatment of diabetic cardiac damage via activation of Erk1/2-P38 MAPK-AMPK signaling.

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CU06-1004 Modulates the Adenosine Monophosphate (AMP)-Associated Protein Kinase (AMPK) Signaling Pathway and Inhibits Lipogenesis in 3T3-L1 Adipocytes and High-Fat Diet-Induced Obese Mice

SSRN Electronic Journal ◽

10.2139/ssrn.3974363 ◽

2021 ◽

Author(s):

Cho-Rong Bae ◽

Young-Guen Kwon

Keyword(s):

Protein Kinase ◽

Signaling Pathway ◽

High Fat Diet ◽

Adenosine Monophosphate ◽

Obese Mice ◽

High Fat ◽

Ampk Signaling

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Crocin Improves Insulin Sensitivity and Ameliorates Adiposity by Regulating AMPK-CDK5-PPARγ Signaling

BioMed Research International ◽

10.1155/2020/9136282 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Kai Fang ◽

Ming Gu

Keyword(s):

Protein Level ◽

Biological Activities ◽

Protective Effects ◽

Metabolic Dysfunction ◽

Ampk Activation ◽

Diabetic Mice ◽

Wild Type ◽

Ampk Signaling ◽

Beneficial Effects

Crocin is a carotenoid compound which possesses multiple biological activities. Our and other laboratory’s previous findings show that crocin alleviates obesity and type 2 diabetes-related complications. We have found that crocin activates AMP-activated protein kinase (AMPK) signaling and inhibition of AMPK suppresses crocin-induced protective effects. However, the causal role of AMPK activation in the biological role of crocin is still not verified. In the present study, we showed that crocin markedly inhibits the changes of glucose metabolic parameters and serum lipid profiles in wild type diabetic mice. In AMPKα KO diabetic mice, those protective effects of crocin against glucose and lipid metabolic dysfunction were abolished. These results demonstrated AMPK activation was responsible for the beneficial effects of crocin on metabolic dysfunction. Moreover, we have shown that the antiobese effect of crocin has been abolished by the deficiency of AMPKα. We also showed that crocin induced a significant decrease of CDK5 protein level in wild type diabetic mice, while this effect was abolished in AMPKα KO diabetic mice. The regulation of downstream targets of CDK5/PPARγ by crocin was abolished by the deficiency of AMPK. In conclusion, our study verified that activation of AMPK is involved in crocin-induced protective effects against glucose and lipid metabolic dysfunction. Activation of AMPK downregulates the protein level of CDK5, followed by the decrease of PPARγ phosphorylation, leading to the inhibition of adipose formation and metabolic dysfunction. Our study provides new insights into the mechanism of protective effects of crocin and interaction of AMPK and CDK5/PPARγ signaling.

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