scholarly journals Critical role of matrix metalloprotease-9 in chronic high fat diet-induced cerebral vascular remodelling and increase of ischaemic brain injury in mice

2014 ◽  
Vol 103 (4) ◽  
pp. 473-484 ◽  
Author(s):  
J. Deng ◽  
J. Zhang ◽  
C. Feng ◽  
L. Xiong ◽  
Z. Zuo
Keyword(s):  
Brain Injury ◽  
High Fat Diet ◽  
Critical Role ◽  
Matrix Metalloprotease ◽  
Vascular Remodelling ◽  
High Fat ◽  
Ischaemic Brain ◽  
Ischaemic Brain Injury ◽  
Cerebral Vascular

scholarly journals CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice

2019 ◽  
Vol 317 (6) ◽  
pp. E973-E983 ◽  
Author(s):  
Annie Hasib ◽  
Chandani K. Hennayake ◽  
Deanna P. Bracy ◽  
Aimée R. Bugler-Lamb ◽  
Louise Lantier ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
High Fat Diet ◽  
Critical Role ◽  
Chow Diet ◽  
Wild Type ◽  
High Fat ◽  
Insulin Resistant ◽  
Beneficial Effects

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

scholarly journals Maternal Exposure to High-Fat Diet Induces Long-Term Derepressive Chromatin Marks in the Heart

Nutrients ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 181 ◽  
Author(s):  
Guillaume Blin ◽  
Marjorie Liand ◽  
Claire Mauduit ◽  
Hassib Chehade ◽  
Mohamed Benahmed ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Heart Development ◽  
High Fat Diet ◽  
Target Genes ◽  
Critical Role ◽  
Maternal Exposure ◽  
High Fat ◽  
Cardiac Alterations

Heart diseases are a leading cause of death. While the link between early exposure to nutritional excess and heart disease risk is clear, the molecular mechanisms involved are poorly understood. In the developmental programming field, increasing evidence is pointing out the critical role of epigenetic mechanisms. Among them, polycomb repressive complex 2 (PRC2) and DNA methylation play a critical role in heart development and pathogenesis. In this context, we aimed at evaluating the role of these epigenetic marks in the long-term cardiac alterations induced by early dietary challenge. Using a model of rats exposed to maternal high-fat diet during gestation and lactation, we evaluated cardiac alterations at adulthood. Expression levels of PRC2 components, its histone marks di- and trimethylated histone H3 (H3K27me2/3), associated histone mark (ubiquitinated histone H2A, H2AK119ub1) and target genes were measured by Western blot. Global DNA methylation level and DNA methyl transferase 3B (DNMT3B) protein levels were measured. Maternal high-fat diet decreased H3K27me3, H2Ak119ub1 and DNA methylation levels, down-regulated the enhancer of zeste homolog 2 (EZH2), and DNMT3B expression. The levels of the target genes, isl lim homeobox 1 (Isl1), six homeobox 1 (Six1) and mads box transcription enhancer factor 2, polypeptide C (Mef2c), involved in cardiac pathogenesis were up regulated. Overall, our data suggest that the programming of cardiac alterations by maternal exposure to high-fat diet involves the derepression of pro-fibrotic and pro-hypertrophic genes through the induction of EZH2 and DNMT3B deficiency.

scholarly journals Pathophysiological role of inflammatory molecules in paediatric ischaemic brain injury

2012 ◽  
Vol 42 (7) ◽  
pp. 784-794 ◽  
Author(s):  
Marisol Mirabelli-Badenier ◽  
Vincent Braunersreuther ◽  
Sébastien Lenglet ◽  
Katia Galan ◽  
Edvige Veneselli ◽  
...  
Keyword(s):  
Brain Injury ◽  
Ischaemic Brain ◽  
Pathophysiological Role ◽  
Inflammatory Molecules ◽  
Ischaemic Brain Injury

scholarly journals Endothelial TFEB (Transcription Factor EB) Improves Glucose Tolerance via Upregulation of IRS (Insulin Receptor Substrate) 1 and IRS2

2020 ◽  
Author(s):  
Jinjian Sun ◽  
Haocheng Lu ◽  
Wenying Liang ◽  
Guizhen Zhao ◽  
Lu Ren ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Insulin Receptor Substrate ◽  
High Fat ◽  
Transcription Factor Eb

Objective: Vascular endothelial cells (ECs) play a critical role in maintaining vascular homeostasis. Aberrant EC metabolism leads to vascular dysfunction and metabolic diseases. TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, has protective effects on vascular inflammation and atherosclerosis. However, the role of endothelial TFEB in metabolism remains to be explored. In this study, we sought to investigate the role of endothelial TFEB in glucose metabolism and underlying molecular mechanisms. Approach and Results: To determine whether endothelial TFEB is critical for glucose metabolism in vivo, we utilized EC-selective TFEB knockout and EC-selective TFEB transgenic mice fed a high-fat diet. EC-selective TFEB knockout mice exhibited significantly impaired glucose tolerance compared with control mice. Consistently, EC-selective TFEB transgenic mice showed improved glucose tolerance. In primary human ECs, small interfering RNA-mediated TFEB knockdown blunts Akt (AKT serine/threonine kinase) signaling. Adenovirus-mediated overexpression of TFEB consistently activates Akt and significantly increases glucose uptake in ECs. Mechanistically, TFEB upregulates IRS1 and IRS2 (insulin receptor substrate 1 and 2). TFEB increases IRS2 transcription measured by reporter gene and chromatin immunoprecipitation assays. Furthermore, we found that TFEB increases IRS1 protein via downregulation of microRNAs (miR-335, miR-495, and miR-548o). In vivo, Akt signaling in the skeletal muscle and adipose tissue was significantly impaired in EC-selective TFEB knockout mice and consistently improved in EC-selective TFEB transgenic mice on high-fat diet. Conclusions: Our data revealed a critical role of TFEB in endothelial metabolism and suggest that TFEB constitutes a potential molecular target for the treatment of vascular and metabolic diseases.

scholarly journals The Role of Substance P in Ischaemic Brain Injury

2013 ◽  
Vol 3 (4) ◽  
pp. 123-142 ◽  
Author(s):  
Renée Turner ◽  
Robert Vink
Keyword(s):  
Brain Injury ◽  
Substance P ◽  
Ischaemic Brain ◽  
Ischaemic Brain Injury

scholarly journals m6A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes

2020 ◽  
Author(s):  
Yuhuan Li ◽  
Qingyang Zhang ◽  
Guanshen Cui ◽  
Fang Zhao ◽  
Xin Tian ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Liver Lipid ◽  
Critical Role ◽  
Biological Processes ◽  
High Fat ◽  
Rna Methylation ◽  
Key Factor

AbstractN6-methyladenosine (m6A) RNA methylation is one of the most abundant modifications on mRNAs and plays an important role in various biological processes. The formation of m6A is catalysed by a methyltransferase complex containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m6A modification in liver lipid and glucose metabolism remain unclear. Here, we show that both Mettl3 expression and m6A level increased in the liver of mice with High Fat Diet (HFD)-induced metabolic disorders, and overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. Hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m6A loss causes extended RNA half-lives of metabolism-related genes, consequently protects mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m6A in HFD-induced metabolic disorders and hepatogenous diabetes.

scholarly journals Critical role of the C5a-activated neutrophils in high-fat diet-induced vascular inflammation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Mizuko Osaka ◽  
Shunsuke Ito ◽  
Masaki Honda ◽  
Yukihiro Inomata ◽  
Kensuke Egashira ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Vascular Inflammation ◽  
Critical Role ◽  
High Fat ◽  
Activated Neutrophils
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