scholarly journals Possible Involvement of Adipose Tissue in Older and Obese Diabetic Patients with Coronavirus SARS-CoV-2 Infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of Hyperinsulinemia Management in COVID-19

2021 ◽  
Author(s):  
Jihoon Shin ◽  
Shinichiro Toyoda ◽  
Shigeki Nishitani ◽  
Atsunori Fukuhara ◽  
Shunbun Kita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Scientific Evidence ◽  
Sglt2 Inhibitor ◽  
Underlying Mechanism ◽  
Spike Protein ◽  
Diabetic Patients ◽  
Environmental Interventions ◽  
Obesity And Diabetes ◽  
Cell Surface Grp78

Aging, obesity and diabetes are major risk factors for the severe progression and outcome of SARS-CoV-2 infection (COVID-19), but the underlying mechanism is not yet fully understood. In this study, we found that the SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes the binding to and accumulation in ACE2-expressing cells. GRP78 was highly expressed in adipose tissue and increased in older and obese diabetic human and mouse subjects. The overexpression of GRP78 was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress-responsive transcription factor XBP-1s. Management of hyperinsulinemia by pharmacological approaches, including metformin, SGLT2 inhibitor or β3-adrenergic receptor agonist, decreased GRP78 gene expression in adipose tissue. Environmental interventions, including exercise, calorie restriction, fasting or cold exposure, reduced the gene expression of GRP78 in adipose tissue. This study provides scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in older and obese diabetic patients. The management of hyperinsulinemia and the related GRP78 expression could be a potential therapeutic or preventative target.<br>

scholarly journals Possible Involvement of Adipose Tissue in Older and Obese Diabetic Patients with Coronavirus SARS-CoV-2 Infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of Hyperinsulinemia Management in COVID-19

2021 ◽  
Author(s):  
Jihoon Shin ◽  
Shinichiro Toyoda ◽  
Shigeki Nishitani ◽  
Atsunori Fukuhara ◽  
Shunbun Kita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Scientific Evidence ◽  
Sglt2 Inhibitor ◽  
Underlying Mechanism ◽  
Spike Protein ◽  
Diabetic Patients ◽  
Environmental Interventions ◽  
Obesity And Diabetes ◽  
Cell Surface Grp78

Aging, obesity and diabetes are major risk factors for the severe progression and outcome of SARS-CoV-2 infection (COVID-19), but the underlying mechanism is not yet fully understood. In this study, we found that the SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes the binding to and accumulation in ACE2-expressing cells. GRP78 was highly expressed in adipose tissue and increased in older and obese diabetic human and mouse subjects. The overexpression of GRP78 was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress-responsive transcription factor XBP-1s. Management of hyperinsulinemia by pharmacological approaches, including metformin, SGLT2 inhibitor or β3-adrenergic receptor agonist, decreased GRP78 gene expression in adipose tissue. Environmental interventions, including exercise, calorie restriction, fasting or cold exposure, reduced the gene expression of GRP78 in adipose tissue. This study provides scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in older and obese diabetic patients. The management of hyperinsulinemia and the related GRP78 expression could be a potential therapeutic or preventative target.<br>

scholarly journals Activation of the S100A7/RAGE Pathway by IGF-1 Contributes to Angiogenesis in Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 621
Author(s):  
Maria Grazia Muoio ◽  
Marianna Talia ◽  
Rosamaria Lappano ◽  
Andrew H. Sims ◽  
Veronica Vella ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Bioinformatic Analysis ◽  
Tube Formation ◽  
Endothelial Cell Proliferation ◽  
Diabetic Patients ◽  
Obesity And Diabetes ◽  
Er Positive

Background: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. Methods: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. Results: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. Conclusions: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.

scholarly journals Potential of Syzygium polyanthum (Daun Salam) in Lowering Blood Glucose Level: A Review

2021 ◽  
Vol 29 (4) ◽  
Author(s):  
Nur Salsabeela Mohd Rahim ◽  
Ida Farah Ahmad ◽  
Terence Yew Chin Tan
Keyword(s):  
Blood Glucose ◽  
Scientific Evidence ◽  
Safety Evaluation ◽  
Underlying Mechanism ◽  
Glucose Absorption ◽  
Diabetic Patients ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Herbal Decoction ◽  
Intestinal Glucose Absorption

Syzygium polyanthum is a herb widely used in Malaysia and Indonesia in cuisines. Traditionally, the herbal decoction of S. polyanthum (daun salam) leaves is often used by diabetic patients in Indonesia. Therefore, our objective is to evaluate the scientific evidence available for S. polyanthum in lowering blood glucose levels (BGL). We systematically searched Pubmed, Google Scholar, Scopus, CENTRAL. LILAC and clinicaltrials.gov databases up to 23rd October 2020 using the keywords “Syzygium polyanthum” and “antidiabetic”. From the selected 413 articles, eight studies involving rodents were included. All results showed a significant effect in lowering BGL without any adverse effects. The possible underlying mechanism of action is attributed to inhibiting intestinal glucose absorption and enhancing glucose uptake by the muscles. Chemical families responsible for the effect were determined as flavonoids, alkaloids and terpenoids. Thus, S. polyanthum leaves showed potential antidiabetic properties, but further research is required to identify the active compounds followed by the safety evaluation of this compound.

Regulation of obese gene expression in KK mice and congenic lethal yellow obese KKAy mice

1996 ◽  
Vol 271 (2) ◽  
pp. E333-E339 ◽  
Author(s):  
M. Hayase ◽  
Y. Ogawa ◽  
G. Katsuura ◽  
H. Shintaku ◽  
K. Hosoda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Tissue Expression ◽  
Mouse Strains ◽  
Mrna Levels ◽  
Ob Gene ◽  
Kk Mice ◽  
Kkay Mice ◽  
Obesity And Diabetes ◽  
Lethal Yellow

To elucidate the regulation of obese (ob) gene expression in obesity and diabetes, we examined ob gene expression in KK mice and congenic lethal yellow obese KKAy mice. Northern blot analysis revealed that the ob mRNA levels are roughly equivalent in each of the epididymal, mesenteric, and subcutaneous white adipose tissue (WAT) from KK and KKAy mice at 4 wk of age, when the obese phenotype of KKAy mice was not apparent. Expression of the ob gene was augmented in the mesenteric and subcutaneous WAT but was unchanged in the epididymal WAT in KKAy mice at 12 wk of age, when KKAy mice developed marked obesity with hyperglycemia, hyperlipidemia, and hyperinsulinemia. The ob gene expression was also examined during fasting in 12-wk-old KK and KKAy mice. After 24 or 72 h of fasting in both mouse strains, ob gene expression was downregulated in the epididymal and mesenteric WAT but was unchanged in the subcutaneous WAT. The present study demonstrates that adipose tissue expression of the ob gene is regulated depending on the nutritional status in KK and KKAy mice.

scholarly journals Meteorin-Like Protein (Metrnl) in Obesity, during Weight Loss and in Adipocyte Differentiation

2021 ◽  
Vol 10 (19) ◽  
pp. 4338
Author(s):  
Andreas Schmid ◽  
Thomas Karrasch ◽  
Andreas Schäffler
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Mrna Expression ◽  
Adipocyte Differentiation ◽  
Specific Effect ◽  
Morbidly Obese ◽  
Diabetic Patients ◽  
Omega 3

Meteorin-like protein (Metrnl) is an adipo-myokine with pleiotropic effects in adipose tissue (AT). Its systemic regulation in obesity and under weight loss is unclear. Circulating Metrnl concentrations were analyzed by ELISA in severely obese patients undergoing bariatric surgery (BS) or low calorie diet (LCD). Metrnl mRNA expression was analyzed in human and murine tissues and cell lines by quantitative real-time PCR. About 312 morbidly obese individuals underwent BS (n = 181; BMI 53.4 + 6.8 kg/m2) or LCD (n = 131; BMI 43.5 + 6.7 kg/m2). Serum samples were obtained at baseline and 3, 6, and 12 months after intervention. AT specimen from subcutaneous and visceral adipose tissue were resected during BS. Serum Metrnl levels were lower in type 2 diabetic patients and negatively correlated with HbA1c. In BS and LCD patients, Metrnl concentrations significantly increased after 3 months and returned to baseline levels after 12 months. There was no gender-specific effect. Metrnl mRNA expression did not differ between visceral and subcutaneous AT in n = 130 patients. In contrast, Metrnl gene expression in mice was highest in intra-abdominal AT followed by subcutaneous, peri-renal, and brown AT. In the murine 3T3-L1 cell line, Metrnl expression was high in pre-adipocytes and mature adipocytes with a transient downregulation during adipocyte differentiation. Metrnl expression remained unaffected upon treatment with glucose, insulin, fatty acids, bile acids, and incretins. Polyunsaturated omega-3 and omega-6 fatty acids downregulated Metrnl expression. Systemic Metrnl is transiently upregulated during massive weight loss and gene expression in adipocytes is differentially regulated.

scholarly journals Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia

2019 ◽  
Author(s):  
Mitsugu Shimobayashi ◽  
Sunil Shetty ◽  
Irina C. Frei ◽  
Bettina K. Wölnerhanssen ◽  
Diana Weissenberger ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Blood Glucose ◽  
Underlying Mechanism ◽  
Glycolytic Enzyme ◽  
Diabetic Patients ◽  
Loss Of Function ◽  
Hexokinase 2 ◽  
High Blood Glucose ◽  
Glucose Levels ◽  
Blood Glucose Levels

AbstractChronically high blood glucose (hyperglycemia) leads to diabetes, fatty liver disease, and cardiovascular disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. Here we show that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in adipose tissue. Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in liver, a condition known as selective insulin resistance, leading to glucose intolerance. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to loss of HK2 by inhibiting translation of Hk2 mRNA. Our findings identify adipose HK2 as a critical mediator of systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved, non-cell-autonomous mechanism for the development of hyperglycemia.One Sentence SummaryLoss of the glycolytic enzyme Hexokinase 2 in adipose tissue is a mechanism underlying high blood glucose levels.

scholarly journals The localization of HPV and CMV in the adipose tissues of female diabetic type 1 rats and the possibility of having a role of reactivity of COVID-19 in diabetic subjects as a new medical hypothesis

2020 ◽  
Vol 10 (3) ◽  
pp. 71-73
Author(s):  
Ahed J Alkhatib
Keyword(s):  
Adipose Tissue ◽  
Synergistic Effects ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Obesity And Diabetes ◽  
Diabetic Model ◽  
Medical Hypothesis ◽  
The Impact

Introduction: Diabetes has various impacts on human body. It is thought that diabetes is predisposed by obesity. Obesity may due to several factors including genetically-environmental factors. The recent views that viruses may act as etiology for obesity. Study objectives: The main objectives of the present study were to investigate the possibility that CMV and HPV of having a role in initiating episodes of obesity and diabetes, and to test the hypothesis that co-existence of multi-viruses including corona virus may work synergistically to increase the impact of COVID-19 on diabetic patients. Methodology: In this study, a diabetic model was induced, the localization of HPV and CMV was determined using immunohistochemistry. Results: Study findings showed that both viruses HPV and CMV exist in the adipose tissue of diabetic rats. Both viruses were brown in color. Conclusions: Taken together, both CMV and HPV exist in the adipose tissue of diabetic rats, and this may explain the phenomenon of autoimmunity in diabetes from one side and from another side, we may explain the occurrence of synergistic effects of COVID-19 virus and the other viruses mentioned in this study.

scholarly journals Bariatric surgery can acutely modulate ER-stress and inflammation on subcutaneous adipose tissue in non-diabetic patients with obesity

2020 ◽  
Author(s):  
Rafael Ferraz-Bannitz ◽  
Caroline Rossi Welendorf ◽  
Priscila Oliveira Coelho ◽  
Wilson Salgado ◽  
Carla Barbosa Nonino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Bariatric Surgery ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Diabetic Patients ◽  
Peroxisome Proliferator ◽  
Strong Positive Correlation ◽  
Peroxisome Proliferator Activated Receptor

Abstract Background Bariatric surgery, especially Roux-en-Y gastric bypass (RYGB) is the most effective and durable treatment option for population with severe obesity. The mechanisms involving adipose tissue may be important to explain the effects of surgery. Methods We aimed to identify the genetic signatures of adipose tissue in patients undergoing RYGB. We evaluated 13 obese, non-diabetic patients (mean age 37 years, 100% women, Body mass index (BMI) 42.2 kg/m2) one day before surgery, 3 and 6 months (M) after RYGB. Results Analysis of gene expression in adipose tissue collected at surgery compared with samples collected at 3M and 6M Post-RYGB showed that interleukins (Interleukin 6, Tumor necrosis factor-α (TNF-α), and Monocyte chemoattractant protein-1(MCP1)) and endoplasmic reticulum stress (ERS) genes (Eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3) and Calreticulin (CALR)) decreased during the follow-up (P ≤ 0.01 for all). Otherwise, genes involved in energy homeostasis (Adiponectin and AMP-activated protein kinase (AMPK)), cellular response to oxidative stress (Sirtuin 1, Sirtuin 3, and Nuclear factor erythroid 2-related factor 2 (NRF2)), mitochondrial biogenesis (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)) and amino acids metabolism (General control nonderepressible 2 (GCN2)) increased from baseline to all other time points evaluated (P ≤ 0.01 for all). Also, expression of Peroxisome proliferator activated receptor gamma (PPARϒ) (adipogenesis regulation) was significantly decreased after RYGB (P < 0.05) We also observed a strong positive correlation between PGC1α, SIRT1 and AMPK with BMI at 3M (P ≤ 0.01 for all) and ADIPOQ and SIRT1 with BMI at 6M (P ≤ 0.01 for all). Conclusions Our findings demonstrate that weight loss is associated with amelioration of inflammation and ERS and increased protection against oxidative stress in adipose tissue. These observations are strongly correlated with a decrease in BMI and essential genes that control cellular energy homeostasis, suggesting an adaptive process on a gene expression level during the caloric restriction and weight loss period after RYGB.

scholarly journals Hypoxia Inhibits Cavin-1 and Cavin-2 Expression and Down-Regulates Caveolae in Adipocytes

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 789-801 ◽  
Author(s):  
Claire Regazzetti ◽  
Karine Dumas ◽  
Sandra Lacas-Gervais ◽  
Faustine Pastor ◽  
Pascal Peraldi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Hypoxia Inducible Factor ◽  
Insulin Receptors ◽  
Underlying Mechanism ◽  
Epididymal Adipose Tissue ◽  
Diabetic Patients ◽  
Model Assessment ◽  
Hypoxia Inducible Factor 1

Abstract During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistance. To understand the underlying mechanism, we analyzed the involvement of caveolae because they play a crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of cavin-1 and cavin-2 expression in the epididymal adipose tissue. Down-regulation of the expression of cavins in response to hypoxia is dependent on hypoxia-inducible factor-1. Indeed, the inhibition of hypoxia-inducible factor-1 restores the expression of cavins and caveolae formation. Expression of cavins regulates insulin signaling because the silencing of cavin-1 and cavin-2 impairs insulin signaling pathway. In human, cavin-1 and cavin-2 are decreased in the sc adipose tissue of obese diabetic patients compared with lean subjects. Moreover, the expression of cavin-2 correlates negatively with the homeostatic model assessment index of insulin resistance and glycated hemoglobin level. In conclusion, we propose a new mechanism in which hypoxia inhibits cavin-1 and cavin-2 expression, resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance.

scholarly journals Luseogliflozin attenuates neointimal hyperplasia after wire injury in high-fat diet-fed mice via inhibition of perivascular adipose tissue remodeling

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yusaku Mori ◽  
Michishige Terasaki ◽  
Munenori Hiromura ◽  
Tomomi Saito ◽  
Hideki Kushima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Neointimal Hyperplasia ◽  
Sglt2 Inhibitor ◽  
High Fat ◽  
Perivascular Adipose Tissue ◽  
Femoral Arteries ◽  
Low Fat Diet ◽  
Adipose Tissue Remodeling

Abstract Background Excess fat deposition could induce phenotypic changes of perivascular adipose tissue (PVAT remodeling), which may promote the progression of atherosclerosis via modulation of adipocytokine secretion. However, it remains unclear whether and how suppression of PVAT remodeling could attenuate vascular injury. In this study, we examined the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitor, luseogliflozin on PVAT remodeling and neointima formation after wire injury in mice. Methods Wilt-type mice fed with low-fat diet (LFD) or high-fat diet (HFD) received oral administration of luseogliflozin (18 mg/kg/day) or vehicle. Mice underwent bilateral femoral artery wire injury followed by unilateral removal of surrounding PVAT. After 25 days, injured femoral arteries and surrounding PVAT were analyzed. Results In LFD-fed lean mice, neither luseogliflozin treatment or PVAT removal attenuated the intima-to-media (I/M) ratio of injured arteries. However, in HFD-fed mice, luseogliflozin or PVAT removal reduced the I/M ratio, whereas their combination showed no additive reduction. In PVAT surrounding injured femoral arteries of HFD-fed mice, luseogliflozin treatment decreased the adipocyte sizes. Furthermore, luseogliflozin reduced accumulation of macrophages expressing platelet-derived growth factor-B (PDGF-B) and increased adiponectin gene expression. Gene expression levels of Pdgf-b in PVAT were correlated with the I/M ratio. Conclusions Our present study suggests that luseogliflozin could attenuate neointimal hyperplasia after wire injury in HFD-fed mice partly via suppression of macrophage PDGF-B expression in PVAT. Inhibition of PVAT remodeling by luseogliflozin may be a novel therapeutic target for vascular remodeling after angioplasty.

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