scholarly journals Mechanisms of SGLT2 (Sodium-Glucose Transporter Type 2) Inhibition-Induced Relaxation in Arteries From Human Visceral Adipose Tissue

Hypertension ◽  
2020 ◽  
Author(s):  
Alessandro De Stefano ◽  
Manfredi Tesauro ◽  
Nicola Di Daniele ◽  
Giuseppina Vizioli ◽  
Francesca Schinzari ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Glucose Transporter ◽  
Ex Vivo ◽  
Cardiovascular Effects ◽  
Tissue Perfusion ◽  
Obese Patients ◽  
High Potassium ◽  
Visceral Adipose

As novel drug treatments for diabetes have shown favorable cardiovascular effects, interest has mounted with regard to their possible vascular actions, particularly in relation to visceral adipose tissue perfusion and remodeling in obesity. The present study tested the vasorelaxing effect of the SGLT2 (sodium-glucose transporter type 2) inhibitor canagliflozin in arteries from visceral adipose tissue of either nonobese or obese humans and investigated the underlying mechanisms. Also, the vasorelaxing effect of canagliflozin and the GLP-1 (glucagon-like peptide 1) agonist liraglutide were compared in arteries from obese patients. To these purposes, small arteries (116–734 μm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. Canagliflozin elicited a higher concentration-dependent vasorelaxation in arterioles from obese than nonobese individuals ( P =0.02). The vasorelaxing response to canagliflozin was not modified ( P =0.93) by inhibition of nitric oxide synthase (L-NAME) or prostacyclin (indomethacin), or by H 2 O 2 scavenging (catalase); also, canagliflozin-induced relaxation was similar ( P =0.23) in endothelium-intact or -denuded arteries precontracted with high potassium concentration, thereby excluding an involvement of endothelium-derived hyperpolarizing factors. The vasorelaxing response to canagliflozin was similar to that elicited by the Na + /H + exchanger 1 inhibitor BIX ( P =0.67), but greater than that to the Na + /Ca ++ exchanger inhibitor SEA 0400 ( P =0.001), hinting a role of Na + /H + exchanger inhibition in canagliflozin-induced relaxation. In arterioles from obese patients, the vasorelaxing response to canagliflozin was greater than that to liraglutide ( P =0.004). These findings demonstrate that canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue, thereby suggesting that SGLT2 inhibition might favorably impact the processes linking visceral adipose burden to vascular disease in obesity.

scholarly journals Systemic Oxidative Stress and Visceral Adipose Tissue Mediators of NLRP3 Inflammasome and Autophagy Are Reduced in Obese Type 2 Diabetic Patients Treated with Metformin

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 892
Author(s):  
Zaida Abad-Jiménez ◽  
Sandra López-Domènech ◽  
Rubén Díaz-Rúa ◽  
Francesca Iannantuoni ◽  
Segundo Ángel Gómez-Abril ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Diabetic Patients ◽  
Low Grade ◽  
Obese Patients ◽  
Visceral Adipose

Obesity is a low-grade inflammatory condition affecting a range of individuals, from metabolically healthy obese (MHO) subjects to type 2 diabetes (T2D) patients. Metformin has been shown to display anti-inflammatory properties, though the underlying molecular mechanisms are unclear. To study whether the effects of metformin are mediated by changes in the inflammasome complex and autophagy in visceral adipose tissue (VAT) of obese patients, a biopsy of VAT was obtained from a total of 68 obese patients undergoing gastric bypass surgery. The patients were clustered into two groups: MHO patients and T2D patients treated with metformin. Patients treated with metformin showed decreased levels of all analyzed serum pro-inflammatory markers (TNFα, IL6, IL1β and MCP1) and a downwards trend in IL18 levels associated with a lower production of oxidative stress markers in leukocytes (mitochondrial ROS and myeloperoxidase (MPO)). A reduction in protein levels of MCP1, NFκB, NLRP3, ASC, ATG5, Beclin1 and CHOP and an increase in p62 were also observed in the VAT of the diabetic group. This downregulation of both the NLRP3 inflammasome and autophagy in VAT may be associated with the improved inflammatory profile and leukocyte homeostasis seen in obese T2D patients treated with metformin with respect to MHO subjects and endorses the cardiometabolic protective effect of this drug.

Proteomic analysis of visceral adipose tissue in pre-obese patients with type 2 diabetes

2013 ◽  
Vol 376 (1-2) ◽  
pp. 99-106 ◽  
Author(s):  
Mora Murri ◽  
Maria Insenser ◽  
Maria Rosa Bernal-Lopez ◽  
Pablo Perez-Martinez ◽  
Hector F. Escobar-Morreale ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Proteomic Analysis ◽  
Obese Patients ◽  
Visceral Adipose

Expression of Syntaxin 8 in Visceral Adipose Tissue Is Increased in Obese Patients with Type 2 Diabetes and Related to Markers of Insulin Resistance and Inflammation

2015 ◽  
Vol 46 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Andoni Lancha ◽  
Santiago López-Garrido ◽  
Amaia Rodríguez ◽  
Victoria Catalán ◽  
Beatriz Ramírez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Obese Patients ◽  
Visceral Adipose

Overexpression of hepatic 5α-reductase and 11β-hydroxysteroid dehydrogenase type 1 in visceral adipose tissue is associated with hyperinsulinemia in morbidly obese patients

Metabolism ◽  
2011 ◽  
Vol 60 (12) ◽  
pp. 1775-1780 ◽  
Author(s):  
René Baudrand ◽  
José Miguel Domínguez ◽  
Cristian A. Carvajal ◽  
Arnoldo Riquelme ◽  
Carmen Campino ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Hydroxysteroid Dehydrogenase ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Visceral Adipose

Abstract 17843: Visceral Adipose Tissue Secretion of Adiponectin Decreases with Increased Body Mass Index

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Lenore R Rengel ◽  
Brittaney Obi ◽  
Jon Gould ◽  
Matthew Goldblatt ◽  
Andrew Kastenmeier ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Metabolic Health ◽  
Metabolically Healthy Obese ◽  
Obese Subjects ◽  
Healthy Obese ◽  
Metabolically Healthy ◽  
Visceral Adipose ◽  
Subcutaneous Adipose

Introduction: Peripheral adiposity is associated with better metabolic health and higher plasma adiponectin (ADPN) levels. Since ADPN is secreted mainly by adipose tissue (AT), it is intriguing that higher visceral adipose tissue (VAT) is associated with lower ADPN levels and poor metabolic health. Hypothesis: We hypothesized that various AT depots differ in their ability to secrete ADPN. Methods: Paired AT samples (VAT and subcutaneous adipose tissue (SAT)) were collected from 19 subjects (10 women, 15 obese) undergoing elective abdominal surgery. The samples were cultured and the supernatant was collected after 24 hours. ADPN levels released into the supernatant from VAT and SAT were measured using multiplex methods. Subjects were defined as obese or non-obese (NO) based on BMI > or ≤ 30kg/m2 respectively. Obese subjects were further classified as metabolically unhealthy obese (MUO) or metabolically healthy obese (MHO) based on presence or absence of type 2 diabetes mellitus, hypertension, or cardiovascular disease at the time of surgery. Results: Mean ADPN secretion levels from SAT and VAT were similar in NO subjects (17.3 ± 3.4 vs. 9.8 ± 13.0 ng/mL/mg, p=0.5) whereas the mean ADPN secretion was lower from VAT among obese subjects (15.9 ± 0.8 vs. 4.5 ± 0.2 ng/mL/mg, p=0.0002). ADPN secretion decreased from VAT (r=-0.16) and increased from SAT (r=0.33) with increased BMI (Fig.1). When MHO and MUO were compared, ADPN secretion from VAT in MHO was reduced only slightly (16.1 ± 8.2 vs. 4.0 ± 2.0 ng/mL/mg, p=0.07) whereas ADPN secretion was significantly reduced in MUO (15.9 ± 5.3 vs. 4.7 ± 4.6 ng/mL/mg, p=0.003). Conclusions: Reduced ADPN secretion from VAT in subjects with increasing BMI may explain lower circulating ADPN levels in obese individuals. Higher ADPN production from SAT and the relatively preserved secretion of ADPN from VAT may explain metabolic health in some obese individuals. Futures studies will help identify factors that control ADPN secretion from AT.

Excess of visceral adipose tissue with or without aortic elongation leads to a steeper heart position

2021 ◽  
pp. 028418512110340
Author(s):  
S Petteri Kauhanen ◽  
Petri Saari ◽  
Tarmo Korpela ◽  
Timo Liimatainen ◽  
Ritva Vanninen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Interquartile Range ◽  
Obese Patients ◽  
Aortic Diseases ◽  
Clinical Value ◽  
Abdominal Aortic ◽  
History Of ◽  
Axial Ct ◽  
Visceral Adipose

Background The heart’s position determined as the heart–aorta angle (HAA) has been demonstrated to associate with ascending aortic (AA) dilatation. Visceral adipose tissue (VAT) and aortic elongation may shift the heart to the steeper position. Purpose To investigate whether VAT and aortic length influence the HAA. Material and Methods We examined 346 consecutive patients (58.4% men; mean age = 67.0 ± 14.1 years) who underwent aortic computed tomography angiography (CTA). HAA was measured as the angle between the long axis of the heart and AA midline. The amount of VAT was measured at the level of middle L4 vertebra from a single axial CT slice. Aortic length was measured by combining four anatomical segments in different CTA images. The amount of VAT and aortic length were determined as mild with values in the lowest quartile and as excessive with values in the other three quartiles. Results A total of 191 patients (55.2%) had no history of aortic diseases, 134 (38.7%) displayed AA dilatation, 8 (2.3%) had abdominal aortic aneurysm (AAA), and 13 (3.8%) had both AA dilatation and AAA. There was a strong nonlinear regression between smaller HAA and VAT/height, and HAA and aortic length/height. Median HAA was 124.2° (interquartile range 119.0°–130.8°) in patients with a mild amount of VAT versus 120.5° (interquartile range 115.4°–124.7°) in patients with excessive VAT ( P < 0.001). Conclusion An excessive amount of VAT and aortic elongation led to a steeper heart position. These aspects may possess clinical value when evaluating aortic diseases in obese patients.

scholarly journals Multinucleated giant cells in adipose tissue are specialized in adipocyte degradation

2020 ◽  
Author(s):  
Ada Admin ◽  
Julia Braune ◽  
Andreas Lindhorst ◽  
Janine Fröba ◽  
Constance Hobusch ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Ex Vivo ◽  
Giant Cells ◽  
Low Grade ◽  
Adipose Tissue Macrophages ◽  
Visceral Adipose ◽  
Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation in visceral adipose tissue (AT) characterized by an increasing number of adipose tissue macrophages (ATMs) and linked to type 2 diabetes. AT inflammation is histologically indicated by the formation of so-called crown-like structures (CLS), as accumulation of ATMs around dying adipocytes, and the occurrence of multi-nucleated giant cells (MGCs). However to date, the function of MGCs in obesity is unknown. Hence, the aim of this study was to characterize MGCs in AT and unravel the function of these cells. <p>We demonstrate that MGCs occur in obese patients and after 24 weeks of high fat diet (HFD) in mice, accompanying signs of AT inflammation and then represent ~3% of ATMs in mice. Mechanistically, we found evidence that adipocyte death triggers MGC formation. Most importantly, MGCs in obese AT have a higher capacity to phagocytose oversized particles, such as adipocytes, as shown by live-imaging of AT, 45 µm bead uptake <i>ex vivo</i> and a higher lipid content <i>in vivo</i>. Finally, we show that IL-4 treatment is sufficient to increase the number of MGCs in AT, whereas other factors maybe more important for endogenous MGC formation <i>in vivo</i>.</p>

Abstract 14315: New Insights Into the Mechanisms of Sepsis: The Role of Proprotein Convertase Subtilisin/kexin Type 9 as a Key Regulator of Pathogen Toxin Clearance

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Elena Topchiy ◽  
Yingjin Wang ◽  
John Boyd ◽  
Keith R Walley
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Ex Vivo ◽  
Fluorescent Microscopy ◽  
Hepatic Uptake ◽  
Cardiovascular Complications ◽  
Proprotein Convertase ◽  
Bacterial Endotoxins ◽  
Visceral Adipose

Background: To prevent severe inflammation during infection, the patient must quickly clear bacterial endotoxins from the circulation before they accumulate and are able to interact with immune cells and vascular endothelium, and induce inflammatory organ failure. Bacterial endotoxins are carried within lipoprotein particles. Thus, one mechanism of action for sepsis treatments could be acceleration of lipoprotein clearance by adipocytes and hepatocytes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases the rate of lipoprotein clearance. We have recently reported that reduced function of PCSK9 improves outcome and prevents cardiovascular complications associated with sepsis. Hypothesis: PCSK9 inhibits LDL associated LPS clearance through hepatic LDLR and VLDL associated LPS clearance through adipose VLDLR. Methods and Results: Using siRNA against the LDLR in HepG2 hepatocytes decreased uptake of fluorescently labeled LPS (fLPS) after 48 hours by 1.50±0.10 fold (n=3, p<0.05). Addition of recombinant PCSK9 in the absence of LDLR did not alter uptake of LPS. We confirmed that hepatic uptake of LPS is exclusively via the LDLR by fluorescent microscopy of ex vivo LPS treated primary hepatocytes isolated from LDLR -/- mice. To address the importance of the LDLR upon clearance of LPS from plasma, we injected fLPS into the portal vein of LDLR-/-, PCSK9-/- and wild type mice (WT). Compared to WT, LDLR-/- mice had 36±13% (n=9, p<0.001) increase in plasma LPS after 1 hour, whereas PCSK9-/- show a significant decrease (28±4%, n=9, p<0.001) in plasma LPS. LDLR-/-, but not PCSK9-/- mice showed 46±7% decrease (n=10, p<0.05) in hepatic uptake. On the other hand, compared to the WT PCSK9-/- mice had 200±35% (n=8, p<0.001) increase in LPS uptake by visceral adipose tissue whereas LDLR-/- had no effect compared to WT mice. To further investigate LPS uptake by adipose tissue we injected flLPS into the tail vein of VLDLR-/- and WT mice. VLDLR-/- mice had 33±6% (n=10, p<0.001) decrease in visceral adipose tissue uptake, with no significant change in hepatic uptake. Conclusions: Expression of hepatic LDLR and adipose VLDLR is mainly regulated by PCSK9 and both play important role in clearing LPS from circulation.

Epigenetic Downregulation of FASN in Visceral Adipose Tissue of Insulin Resistant Subjects

2020 ◽  
Author(s):  
Helen Sievert ◽  
Christin Krause ◽  
Cathleen Geißler ◽  
Martina Grohs ◽  
Alexander T. El-Gammal ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
Visceral Adipose Tissue ◽  
High Hba1c ◽  
Obese Subjects ◽  
Visceral Adipose

Abstract Objective The risk to develop type 2 diabetes increases with the amount of visceral adiposity presumably due to increased lipolysis and subsequent lipid accumulation in visceral organs. However, data describing the molecular regulation of these pathways in humans are rare. We tested if genes of the lipogenic and lipolytic pathways are associated with glucose intolerance independently of obesity in visceral adipose tissue (VAT) of obese subjects. Moreover, we studied DNA methylation of FASN (fatty acid synthase), that catalyses the synthesis of long-chain fatty acids, in VAT of the same subjects and whether it is associated with metabolic traits. Subjects and methods Visceral adipose tissue biopsies and blood samples were taken from 93 severely obese subjects undergoing bariatric surgery. Subjects were grouped in low HbA1c (L-HbA1c, HbA1c<6.5 %) and high HbA1c (H-HbA1c, HbA1c≥6.5 %) groups and expression of genes from the lipogenic and lipolytic pathways was analysed by TaqMan qPCR. DNA methylation of FASN was quantified by bisulfite-pyrosequencing. Results FASN expression was downregulated in visceral fat from subjects with high HbA1c (p = 0.00009). Expression of other lipogenetic (SCD, ELOVL6) or lipolytic genes (ADRB3, PNPLA2) and FABP4 was not changed. DNA methylation of FASN was increased at a regulatory ChoRE recognition site in the H-HbA1c-subgroup and correlated negatively with FASN mRNA (r = − 0.302, p = 0.0034) and positively with HbA1c (r = 0.296, p = 0.0040) and blood glucose (r = 0.363, p = 0.0005). Conclusions Epigenetic downregulation of FASN in visceral adipose tissue of obese subjects might contribute to limited de novo lipogenesis of important insulin sensitizing fatty acids and could thereby contribute to glucose intolerance and the development of type 2 diabetes independently of obesity.

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