A Western diet-induced mouse model reveals a possible mechanism by which metformin decreases obesity

Introduction: Obesity and hepatic VLDL overproduction are key risk factors for the development of dyslipidemia and metabolic inflammatory diseases including atherosclerosis and non-alcoholic fatty liver disease (NAFLD). HB-EGF is a representative mediator for sustained EGFR transactivation under diverse oxidative stress environments including central obesity. A previous report showed that, in C57BL/6 mice, an injection of recombinant HB-EGF significantly increased apoB and TG secretion from the liver; in contrast, HB-EGF antisense oligonucleotide (ASO) administration induced a significant suppression of the hepatic VLDL secretion. Hypothesis: In this study, we tested the hypothesis, which was, that HB-EGF is an autonomous stimulator for the hepatic VLDL production in the liver, which would result in the development of hypertriglyceridemia, causing metabolic inflammatory diseases when under obese and over-nutrition. Methods and Results: In liver-derived cell line HepG2, recombinant HB-EGF treatment induced an autonomous increase of apoB production in the cells. In LDLR deficient mice under a western diet, which showed a list of metabolic syndrome phenotypes, HB-EGF ASO administration induced an effective downregulation of circulatory VLDL and TG level. The HB-EGF ASO administration also showed effective protection against atherosclerosis and non-alcoholic steatohepatitis (NASH) phenotypes in the mouse model. Conclusions: The results suggest that HB-EGF is a positive stimulator of hepatic VLDL production that may cause hypertriglyceridemia under obese and over-nutrition. It was also demonstrated that HB-EGF targeting could be an effective approach to prevent and reverse vascular and hepatic inflammations as shown in a mouse model. Figure: LDLR deficient mice under western diet were treated with control and HB-EGF ASOs for 12 weeks. CD68 positive cell content and inflammatory gene MCP1 transcription level in liver were compared.

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Chronic consumption of a western diet induces robust glial activation in aging mice and in a mouse model of Alzheimer’s disease

Scientific Reports ◽

10.1038/srep21568 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 50

Author(s):

Leah C. Graham ◽

Jeffrey M. Harder ◽

Ileana Soto ◽

Wilhelmine N. de Vries ◽

Simon W. M. John ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Western Diet ◽

Glial Activation ◽

Model Of Alzheimer’S Disease

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Dipeptidyl peptidase inhibition prevents diastolic dysfunction and reduces myocardial fibrosis in a Mouse model of Western diet induced obesity

Metabolism ◽

10.1016/j.metabol.2014.04.002 ◽

2014 ◽

Vol 63 (8) ◽

pp. 1000-1011 ◽

Cited By ~ 68

Author(s):

Brian Bostick ◽

Javad Habibi ◽

Lixin Ma ◽

Annayya Aroor ◽

Nathan Rehmer ◽

...

Keyword(s):

Mouse Model ◽

Diastolic Dysfunction ◽

Myocardial Fibrosis ◽

Dipeptidyl Peptidase ◽

Western Diet ◽

Diet Induced Obesity

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Daily exercise prevents diastolic dysfunction and oxidative stress in a female mouse model of western diet induced obesity by maintaining cardiac heme oxygenase-1 levels

Metabolism ◽

10.1016/j.metabol.2016.09.005 ◽

2017 ◽

Vol 66 ◽

pp. 14-22 ◽

Cited By ~ 15

Author(s):

Brian Bostick ◽

Annayya R. Aroor ◽

Javad Habibi ◽

William Durante ◽

Lixin Ma ◽

...

Keyword(s):

Oxidative Stress ◽

Mouse Model ◽

Diastolic Dysfunction ◽

Heme Oxygenase ◽

Female Mouse ◽

Western Diet ◽

Heme Oxygenase 1 ◽

Diet Induced Obesity ◽

Daily Exercise ◽

And Oxidative Stress

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Fatty Acid Synthase Inhibitor Platensimycin Intervenes the Development of Nonalcoholic-Fatty Liver Disease in a Mouse Model

Biomedicines ◽

10.3390/biomedicines10010005 ◽

2021 ◽

Vol 10 (1) ◽

pp. 5

Author(s):

Meng Su ◽

Danfeng Cao ◽

Zhe Wang ◽

Yanwen Duan ◽

Yong Huang

Keyword(s):

Fatty Acid ◽

Liver Disease ◽

Mouse Model ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Fatty Acid Synthase ◽

Western Diet ◽

World Population ◽

Mrna Levels ◽

Alcoholic Fatty Liver

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting about 25% of world population, while there are still no approved targeted therapies. Although platensimycin (PTM) was first discovered to be a broad-spectrum antibiotic, it was also effective against type II diabetes in animal models due to its ability to inhibit both bacterial and mammalian fatty acid synthases (FASN). Herein, we report the pharmacological effect and potential mode of action of PTM against NAFLD in a Western diet/CCI4-induced mouse model and a free fatty acids (FFAs)-induced HepG2 cell model. The proper dose of PTM and its liposome-based nano-formulations not only significantly attenuated the Western diet-induced weight gain and the levels of plasma total triglycerides and glucose, but reduced liver steatosis in mice according to histological analyses. Western blotting analysis showed a reduced protein level of FASN in the mouse liver, suggesting that PTM intervened in the development of NAFLD through FASN inhibition. PTM reduced both the protein and mRNA levels of FASN in FFAs-induced HepG2 cells, as well as the expression of several key proteins in lipogenesis, including sterol regulatory element binding protein-1, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. The expression of lipid oxidation-related genes, including peroxisome proliferator activated receptor α and acyl-CoA oxidase 1, was significantly elevated. In conclusion, our study supports the reposition of PTM to intervene in NAFLD progression, since it could effectively inhibit de novo lipogenesis.

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Apple polyphenols decrease endothelial dysfunction and atherosclerosis after chronic Western diet in a ApoE mouse model

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2018.02.013 ◽

2018 ◽

Vol 10 (2) ◽

pp. 181 ◽

Cited By ~ 1

Author(s):

G. Bolea ◽

C. Philouze ◽

M. Dubois ◽

A. Humberclaude ◽

C. Ginies ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Mouse Model ◽

Western Diet ◽

Apoe Mouse

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Assessing cortical and subcortical changes in a western diet mouse model using spectral/Fourier domain OCT (Conference Presentation)

Neural Imaging and Sensing ◽

10.1117/12.2251009 ◽

2017 ◽

Author(s):

Marcel T. Bernucci ◽

Jennifer E. Norman ◽

Conrad W. Merkle ◽

Hnin H. Aung ◽

Jennifer Rutkowsky ◽

...

Keyword(s):

Mouse Model ◽

Western Diet ◽

Fourier Domain ◽

Fourier Domain Oct

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Live and Diet by Your Gut Microbiota

mBio ◽

10.1128/mbio.02335-19 ◽

2019 ◽

Vol 10 (5) ◽

Author(s):

Christine M. Bassis

Keyword(s):

Mouse Model ◽

Gut Microbiota ◽

Western Diet ◽

Microbiota Composition ◽

High Fat ◽

Future Studies ◽

Microbiota Analysis ◽

Lethal Sepsis

ABSTRACT Diet influences health in multiple ways. One important effect of diet is on the gut microbiota. The effects of diet are often related to an individual’s specific microbiota composition. The close links between health, diet, and gut microbiota are illustrated in a new mouse model of sepsis where the combination of a high-fat/low-fiber Western diet, antibiotics, and surgery promotes the development of lethal sepsis. Diet can also influence infection via the gut microbiota beyond sepsis. Future studies with this model may inform the use of microbiota analysis and personalized diets to protect surgery patients from infection and sepsis.

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DPP-4 Inhibitor Sitagliptin Improves Cardiac Function and Glucose Homeostasis and Ameliorates β-Cell Dysfunction Together with Reducing S6K1 Activation and IRS-1 and IRS-2 Degradation in Obesity Female Mice

Journal of Diabetes Research ◽

10.1155/2018/3641516 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Shigang Qiao ◽

Guofang Mao ◽

Hua Li ◽

Zhimin Ma ◽

Lei Hong ◽

...

Keyword(s):

Body Weight ◽

Mouse Model ◽

Cardiac Function ◽

Diastolic Dysfunction ◽

Plasma Glucose ◽

Female Mouse ◽

Cell Function ◽

Western Diet ◽

Protective Effects ◽

Cell Dysfunction

Background. Chronic overnutrition leads to cardiac dysfunction and insulin (INS) resistance. Dipeptidyl peptidase-4 (DPP-4) improves glucose metabolism and insulin sensitivity in both human and animal models. In this study, we explored whether DPP-4 inhibitor sitagliptin (SIT) is involved in the protection of cardiac function and β-cell function using an obesity female mouse model. Methods. Six-week-old C57BL6/J mice were fed a high fat and fructose Western diet with DPP-4 inhibitor SIT for 12 weeks. Cardiac function was examined by echocardiography. Body weight, plasma glucose, and insulin concentrations were measured. The contents of total S6 kinase 1 (S6K1), phosphorylation of S6K1 activation, and INS docking proteins INS receptor substrates 1 and 2 (IRS-1, IRS-2) were assayed, and histology of heart tissue was performed. Results. Chronic Western diet consumption elevated plasma glucose and insulin and caused obesity, diastolic dysfunction, and β-cell dysfunction. DPP-4 inhibition with SIT resulted in reduction in body weight, fasting glucose, and plasma insulin, and improved cardiac diastolic dysfunction. SIT also decreased mTOR/S6K1 activation and prevented the degradation of IRS-1 and IRS-2. Conclusions. This study revealed pleiotropic protective effects of DPP-4 inhibitor SIT on cardiac function, glycemia, and β-cell function together with reducing S6K1 activation and IRS-1 and IRS-2 degradation in the obesity female mouse model.

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