scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

scholarly journals Modulatory Effect of Polyphenolic Compounds from the Mangrove Tree Rhizophora mangle L. on Non-Alcoholic Fatty Liver Disease and Insulin Resistance in High-Fat Diet Obese Mice

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2114 ◽  
Author(s):  
Leonardo de Souza Mesquita ◽  
Cíntia Caria ◽  
Paola Santos ◽  
Caio Ruy ◽  
Natalia da Silva Lima ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Rhizophora Mangle ◽  
Mrna Levels ◽  
Obese Mice ◽  
High Fat ◽  
Mangrove Tree

No scientific report proves the action of the phytochemicals from the mangrove tree Rhizophora mangle in the treatment of diabetes. The aim of this work is to evaluate the effects of the acetonic extract of R. mangle barks (AERM) on type 2 diabetes. The main chemical constituents of the extract were analyzed by high-performance liquid chromatography (HPLC) and flow injection analysis electrospray-iontrap mass spectrometry (FIA-ESI-IT-MS/MS). High-fat diet (HFD)-fed mice were used as model of type 2 diabetes associated with obesity. After 4 weeks of AERM 5 or 50 mg/kg/day orally, glucose homeostasis was evaluated by insulin tolerance test (kiTT). Hepatic steatosis, triglycerides and gene expression were also evaluated. AERM consists of catechin, quercetin and chlorogenic acids derivatives. These metabolites have nutritional importance, obese mice treated with AERM (50 mg/kg) presented improvements in insulin resistance resulting in hepatic steatosis reductions associated with a strong inhibition of hepatic mRNA levels of CD36. The beneficial effects of AERM in an obesity model could be associated with its inhibitory α-amylase activity detected in vitro. Rhizophora mangle partially reverses insulin resistance and hepatic steatosis associated with obesity, supporting previous claims in traditional knowledge.

scholarly journals Untargeted Metabolomics Analysis Revealed Lipometabolic Disorders in Perirenal Adipose Tissue of Rabbits Subject to a High-Fat Diet

Animals ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 2289
Author(s):  
Siqi Xia ◽  
Jiahao Shao ◽  
Mauricio A. Elzo ◽  
Tao Tang ◽  
Yanhong Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acids ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Unsaturated Fatty Acids ◽  
High Resolution Mass Spectrometry ◽  
Untargeted Metabolomics ◽  
High Fat

A high-fat diet (HFD) is widely recognized as a significant modifiable risk for insulin resistance, inflammation, Type 2 diabetes, atherosclerosis and other metabolic diseases. However, the biological mechanism responsible for key metabolic disorders in the PAT of rabbits subject to HFD remains unclear. Here, untargeted metabolomics (LC-MS/MS) combined with liquid chromatography (LC) and high-resolution mass spectrometry (MS) were used to evaluate PAT metabolic changes. Histological observations showed that the adipocytes cells and density of PAT were significantly increased in HFD rabbits. Our study revealed 206 differential metabolites (21 up-regulated and 185 down-regulated); 47 differential metabolites (13 up-regulated and 34 down-regulated), comprising mainly phospholipids, fatty acids, steroid hormones and amino acids, were chosen as potential biomarkers to help explain metabolic disorders caused by HFD. These metabolites were mainly associated with the biosynthesis of unsaturated fatty acids, the arachidonic acid metabolic pathway, the ovarian steroidogenesis pathway, and the platelet activation pathway. Our study revealed that a HFD caused significant lipometabolic disorders. These metabolites may inhibit oxygen respiration by increasing the adipocytes cells and density, cause mitochondrial and endoplasmic reticulum dysfunction, produce inflammation, and finally lead to insulin resistance, thus increasing the risk of Type 2 diabetes, atherosclerosis, and other metabolic syndromes.

scholarly journals TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes

2021 ◽  
Vol 22 (19) ◽  
pp. 10647
Author(s):  
Mark Agostino ◽  
Jennifer Rooney ◽  
Lakshini Herat ◽  
Jennifer Matthews ◽  
Allyson Simonds ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Liver Steatosis ◽  
Western World ◽  
Acid Oxidation ◽  
High Fat

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents. In this study, we use in silico approaches to identify key regions of TNFSF14 responsible for binding to the Herpes virus entry mediator and Lymphotoxin β receptor. In vitro evaluation of a selection of optimised peptides identified six potentially therapeutic TNFSF14 peptides. We report that these peptides increased insulin and fatty acid oxidation signalling in skeletal muscle cells. We then selected one of these promising peptides to determine the efficacy to promote metabolic benefits in vivo. Importantly, the TNFSF14 peptide 7 reduced high fat diet-induced glucose intolerance, insulin resistance and hyperinsulinemia in a mouse model of obesity. In addition, we highlight that the TNFSF14 peptide 7 resulted in a marked reduction in liver steatosis and a concomitant increase in phospho-AMPK signalling. We conclude that TNFSF14-derived molecules positively regulate glucose homeostasis and lipid metabolism and may therefore open a completely novel therapeutic pathway for treating obesity and T2D.

Abstract 015: Increased 20-HETE Levels Contribute to Impaired Glucose Metabolism and Type 2 Diabetes in Cyp4a14 Knockout Mice Fed on High Fat Diet.

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Varunkumar G Pandey ◽  
Lars Bellner ◽  
Victor Garcia ◽  
Joseph Schragenheim ◽  
Andrew Cohen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Weight Gain ◽  
Blood Glucose ◽  
High Fat Diet ◽  
Plasma Insulin ◽  
High Fat ◽  
Plasma Insulin Levels

20-HETE (20-Hydroxyeicosatetraenoic acid) is a cytochrome P450 ω-hydroxylase metabolite of arachidonic acid that promotes endothelial dysfunction, microvascular remodeling and hypertension. Previous studies have shown that urinary 20-HETE levels correlate with BMI and plasma insulin levels. However, there is no direct evidence for the role of 20-HETE in the regulation of glucose metabolism, obesity and type 2 diabetes mellitus. In this study we examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water-soluble 20-HETE antagonist, on blood pressure, weight gain and blood glucose in Cyp4a14 knockout (Cyp4a14-/-) mice fed high-fat diet (HFD). The Cyp4a14-/- male mice exhibit high vascular 20-HETE levels and display 20-HETE-dependent hypertension. There was no difference in weight gain and fasting blood glucose between Cyp4a14-/- and wild type (WT) on regular chow. When subjected to HFD for 15 weeks, a significant increase in weight was observed in Cyp4a14-/- as compared to WT mice (56.5±3.45 vs. 30.2±0.7g, p<0.05). Administration of 20-SOLA (10mg/kg/day in drinking water) significantly attenuated the weight gain (28.7±1.47g, p<0.05) and normalized blood pressure in Cyp4a14-/- mice on HFD (116±0.3 vs. 172.7±4.6mmHg, p<0.05). HFD fed Cyp4a14-/- mice exhibited hyperglycemia as opposed to normal glucose levels in WT on a HFD (154±1.9 vs. 96.3±3.0 mg/dL, p<0.05). 20-SOLA prevented the HFD-induced hyperglycemia in Cyp4a14-/- mice (91±8mg/dL, p<0.05). Plasma insulin levels were markedly high in Cyp4a14-/- mice vs. WT on HFD (2.66±0.7 vs. 0.58±0.18ng/mL, p<0.05); corrected by the treatment with 20-SOLA (0.69±0.09 ng/mL, p<0.05). Importantly, glucose and insulin tolerance tests showed impaired glucose homeostasis and insulin resistance in Cyp4a14-/- mice on HFD; ameliorated by treatment with 20-SOLA. This novel finding that blockade of 20-HETE actions by 20-SOLA prevents HFD-induced obesity and restores glucose homeostasis in Cyp4a14-/- mice suggests that 20-HETE contributes to obesity, hyperglycemia and insulin resistance in HFD induced metabolic disorder. The molecular mechanisms underlying 20-HETE mediated metabolic dysfunction are being currently explored.

scholarly journals Establishment of long-term high-fat diet and low dose streptozotocin-induced experimental type-2 diabetes mellitus model of insulin resistance and evaluation of seed extracts of Syzygium cumini

2021 ◽  
Vol 10 (3) ◽  
pp. 331-338
Author(s):  
Pratibha Nadig ◽  
Meharban Asanaliyar ◽  
Kevin Manohar Salis
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
High Fat Diet ◽  
Low Dose ◽  
Syzygium Cumini ◽  
High Fat ◽  
Glut 4 ◽  
Seed Extracts

Introduction: The principal mechanism responsible for reducing blood glucose is through insulin-stimulated glucose transport into skeletal muscle. The transporter protein that mediates this uptake is GLUT-4. A defect in this step is associated with reduced glucose utilization in muscle and adipose tissue, as observed in insulin-resistant type-2 diabetes mellitus (T2DM) patients. This study aimed to develop an experimental T2DM model and evaluate altered glucose transporter type 4 (GLUT-4) levels as a biomarker of insulin resistance. Antidiabetic activities of Syzygium cumini hydro-ethanolic seed extracts (SCE) were also evaluated. Methods: Adult male Wistar albino rats were fed a high-fat diet for 12 weeks and dosed intraperitoneally with streptozotocin (35 mg/kg). After treatment for 21 days, all investigations were done. The homeostasis model of assessment (HOMA) was used for the calculation of insulin resistance (HOMA-IR) and beta-cell function (HOMA-B) index. Diaphragm muscle and retroperitoneal fat were collected for real-time polymerase chain reaction (RT-PCR) studies. Results: A significant increase in fasting blood glucose, HOMA-IR, and serum lipids, and a decrease in serum insulin and HOMA-B were observed in the diabetic group, effects that reversed following pioglitazone and SCE treatment. The diabetic group showed a downregulation of GLUT-4 expression in skeletal muscle while an increase was observed in adipose tissue. Conclusion: A high-fat diet and low dose streptozotocin-induced experimental T2DM model of insulin resistance was developed to screen novel insulin sensitizers. Data generated demonstrated that altered GLUT-4 levels could be used as a biomarker of insulin resistance. Antidiabetic activity of S. cumini hydro-ethanolic seed extract was also confirmed in this study.

The antianginal ranolazine does not confer beneficial actions against hepatic steatosis in male mice subjected to high-fat diet and streptozotocin induced type 2 diabetes

2021 ◽  
Author(s):  
Christina T Saed ◽  
Amanda A Greenwell ◽  
Seyed Amirhossein Tabatabaei Dakhili ◽  
Keshav Gopal ◽  
Farah Eaton ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Low Fat Diet ◽  
Insulin Tolerance ◽  
Triacylglycerol Content ◽  
Hepatic Triacylglycerol

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess fat in the liver in the absence of alcohol and increases one’s risk for both diabetes and cardiovascular disease (e.g. angina). We have shown that the second-line anti-anginal therapy, ranolazine, mitigates obesity-induced NAFLD, and our aim was to determine whether these actions of ranolazine also extend to NAFLD associated with type 2 diabetes (T2D). 8-week-old male C57BL/6J mice were fed either a low-fat diet or a high-fat diet for 15-weeks, with a single dose of streptozotocin (STZ; 75 mg/kg) administered in the high-fat diet fed mice at 4-weeks to induce experimental T2D. Mice were treated with either vehicle control or ranolazine during the final 7-weeks (50 mg/kg once daily). We assessed glycemia via monitoring glucose tolerance, insulin tolerance, and pyruvate tolerance, whereas hepatic steatosis was assessed via quantifying triacylglycerol content. We observed that ranolazine did not improve glycemia in mice with experimental T2D, while also having no impact on hepatic triacylglycerol content. Therefore, the salutary actions of ranolazine against NAFLD may be limited to obese individuals but not those who are obese with T2D.

scholarly journals Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation

2018 ◽  
Vol 19 (9) ◽  
pp. 2706 ◽  
Author(s):  
Cristina Sena ◽  
Maria Cipriano ◽  
Maria Botelho ◽  
Raquel Seiça
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Liver Function ◽  
Hepatic Steatosis ◽  
Lipoic Acid ◽  
High Fat Diet ◽  
Control Group ◽  
High Fat ◽  
Tnf Α

Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.

scholarly journals Purple-leaf tea (Camellia sinensis L.) ameliorates high-fat diet induced obesity and metabolic disorder through the modulation of the gut microbiota in mice

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yu-Chun Lin ◽  
Hsu-Feng Lu ◽  
Jui-Chieh Chen ◽  
Hsiu-Chen Huang ◽  
Yu-Hsin Chen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gut Microbiota ◽  
Camellia Sinensis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Normal Diet ◽  
High Fat ◽  
Hepatic Diseases ◽  
Purple Leaf

Abstract Background Obesity and its associated diseases have become a major world-wide health problem. Purple-leaf Tea (Camellia sinensis L.) (PLT), that is rich of anthocyanins, has been shown to have preventive effects on obesity and metabolic disorders. The intestinal microbiota has been shown to contribute to inflammation, obesity, and several metabolic disorders. However, whether PLT consumption could prevent obesity and diet-induced metabolic diseases by modulating the gut microbiota, is not clearly understood. Methods In this study, six-week-old male C57BL/6 J mice were fed a normal diet (ND) or a high fat diet (HFD) without or with PLT for 10 weeks. Results PLT modulated the gut microbiota in mice and alleviated the symptoms of HFD-induced metabolic disorders, such as insulin resistance, adipocyte hypertrophy, and hepatic steatosis. PLT increased the diversity of the microbiota and the ratio of Firmicutes to Bacteroidetes. f_Barnesiellaceae, g_Barnesiella, f_Ruminococcaceae, and f_Lachnospiraceae were discriminating faecal bacterial communities of the PLT mice that differed from the HFD mice. Conclusions These data indicate that PLT altered the microbial contents of the gut and prevented microbial dysbiosis in the host, and consequently is involved in the modulation of susceptibility to insulin resistance, hepatic diseases, and obesity that are linked to an HFD.

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