High-fat meals do not affect thrombin formation and fibrin clot lysis in individuals with obesity during intentional weight loss

Abstract Background Obesity drives endometrial cancer (EC). Metabolic surgery (MS) induces sustained weight loss, reduces EC risk and has been shown to reverse histological changes of endometrial hyperplasia. One mechanism is increased GLP-1 post surgery. Few interventional studies have been conducted in the BDII/Han rat; an animal model of spontaneous EC. This study aimed to examine whether high fat diet (HFD) and weight gain, as well as subsequent intentional weight loss using Liraglutide (a GLP-1 receptor agonist) alters EC tumour biology and burden in the BDII/Han rat. A rat imaging protocol was validated to assess development and longitudinally track tumours. Methods An imaging protocol was developed and validated. 7 BDII/Han rats were fed normal chow (NC) and 8 weight-matched rats fed HFD from 3 months of age. Longitudinal PET-CT was conducted at 7, 9, 12 and 15 months. Abdominal visceral fat was analysed from L1-L5 on CT. Subsequently, an intervention study compared the 8 HFD-Control rats to 8 weight-matched HFD-fed rats treated with Liraglutide from 12-15 months. PET-CT was used to assess disease progression. Analysis of histological, immunohistochemical and transcriptomic parameters were used to compare cohorts. All rats were euthanased aged 15-months. Imaging was correlated with necropsy findings and histopathology. Results HFD rats had more abdominal fat on CT imaging (8.6cm3±0.7vs4.0cm3±0.6;p<0.0005) and 10% higher body-weight than NC rats (232.5g±4.9vs209.4g±2.0;p=0.001) at the study end. Histopathology demonstrated EC in 57%(n = 4) of NC and 50%(n = 4) of HFD rats. PET-CT was 87.5% sensitive and 86% specific. Liraglutide induced significant reduction in final body weight (208.3g±5.7vs232.5g±4.9;p=0.006) and abdominal fat on CT compared to controls (4.4cm3±0.4vs8.6cm3±0.7; p=0.0001). 2 tumours were identified in the Liraglutide group (25%) compared to 4 in the control group (50%). GLP-1 receptor expression was not detected in benign or malignant BDII/Han uterine tissue. Conclusions This study has established a safe, sensitive and specific imaging protocol for longitudinal assessment of EC progression in BDII/Han rats. The HFD intervention used did not accelerate EC burden. However, it did create an obese phenotype and gave new information on the pathological variations of EC in the BDII/Han rat. Intentional weight loss from Liraglutide halved EC burden compared to controls in this study. An absence of GLP-1R expression may suggest weight loss dependent mechanisms. This novel pilot study is a foundation for future studies assessing the effect of intentional weight loss using metabolic surgery in obesity-related cancer.

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The Roles of α2-Antiplasmin and Plasminogen Activator Inhibitor 1 (PAI-1) in the Inhibition of Clot Lysis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649570 ◽

1993 ◽

Vol 70 (02) ◽

pp. 301-306 ◽

Cited By ~ 51

Author(s):

Linda A Robbie ◽

Nuala A Booth ◽

Alison M Croll ◽

Bruce Bennett

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Fibrin Clot ◽

Clot Lysis ◽

Plasminogen Activator Inhibitor 1 ◽

Dependent Inhibition ◽

Activator Inhibitor ◽

Pai 1

SummaryThe relative importance of the two major inhibitors of fibrinolysis, α2-antiplasmin (α2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified α2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to α2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 × 108/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, α2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of α2-AP, in such situations.

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Incorporation of α2-Plasmin Inhibitor into Fibrin Clots and Its Association with the Clinical Outcome of Acute Ischemic Stroke Patients

Biomolecules ◽

10.3390/biom11030347 ◽

2021 ◽

Vol 11 (3) ◽

pp. 347

Author(s):

Zsuzsa Bagoly ◽

Barbara Baráth ◽

Rita Orbán-Kálmándi ◽

István Szegedi ◽

Réka Bogáti ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Intracranial Hemorrhage ◽

Intravenous Thrombolysis ◽

Fibrin Clot ◽

Clot Lysis ◽

Stroke Patients ◽

Plasmin Inhibitor ◽

Fibrin Clots

Cross-linking of α2-plasmin inhibitor (α2-PI) to fibrin by activated factor XIII (FXIIIa) is essential for the inhibition of fibrinolysis. Little is known about the factors modifying α2-PI incorporation into the fibrin clot and whether the extent of incorporation has clinical consequences. Herein we calculated the extent of α2-PI incorporation by measuring α2-PI antigen levels from plasma and serum obtained after clotting the plasma by thrombin and Ca2+. The modifying effect of FXIII was studied by spiking of FXIII-A-deficient plasma with purified plasma FXIII. Fibrinogen, FXIII, α2-PI incorporation, in vitro clot-lysis, soluble fibroblast activation protein and α2-PI p.Arg6Trp polymorphism were measured from samples of 57 acute ischemic stroke patients obtained before thrombolysis and of 26 healthy controls. Increasing FXIII levels even at levels above the upper limit of normal increased α2-PI incorporation into the fibrin clot. α2-PI incorporation of controls and patients with good outcomes did not differ significantly (49.4 ± 4.6% vs. 47.4 ± 6.7%, p = 1.000), however it was significantly lower in patients suffering post-lysis intracranial hemorrhage (37.3 ± 14.0%, p = 0.004). In conclusion, increased FXIII levels resulted in elevated incorporation of α2-PI into fibrin clots. In stroke patients undergoing intravenous thrombolysis treatment, α2-PI incorporation shows an association with the outcome of therapy, particularly with thrombolysis-associated intracranial hemorrhage.

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Replacing a Palatable High-Fat Diet with a Low-Fat Alternative Heightens κ-Opioid Receptor Control over Nucleus Accumbens Dopamine

Nutrients ◽

10.3390/nu13072341 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2341

Author(s):

Conner W. Wallace ◽

Nari S. Beatty ◽

Sarah A. Hutcherson ◽

Heather A. Emmons ◽

Madison C. Loudermilt ◽

...

Keyword(s):

Weight Loss ◽

Nucleus Accumbens ◽

High Fat Diet ◽

Elevated Plus Maze ◽

High Fat ◽

Food Cravings ◽

Fast Scan Cyclic Voltammetry ◽

Diet Induced Obesity ◽

Plus Maze ◽

Weight Loss Interventions

Diet-induced obesity reduces dopaminergic neurotransmission in the nucleus accumbens (NAc), and stressful weight loss interventions could promote cravings for palatable foods high in fat and sugar that stimulate dopamine. Activation of κ-opioid receptors (KORs) reduces synaptic dopamine, but contribution of KORs to lower dopamine tone after dietary changes is unknown. Therefore, the purpose of this study was to determine the function of KORs in C57BL/6 mice that consumed a 60% high-fat diet (HFD) for six weeks followed by replacement of HFD with a control 10% fat diet for one day or one week. HFD replacement induced voluntary caloric restriction and weight loss. However, fast-scan cyclic voltammetry revealed no differences in baseline dopamine parameters, whereas sex effects were revealed during KOR stimulation. NAc core dopamine release was reduced by KOR agonism after one day of HFD replacement in females but after one week of HFD replacement in males. Further, elevated plus-maze testing revealed no diet effects during HFD replacement on overt anxiety. These results suggest that KORs reduce NAc dopamine tone and increase food-related anxiety during dietary weight loss interventions that could subsequently promote palatable food cravings and inhibit weight loss.

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Navy Bean Supplementation in Established High-Fat Diet-Induced Obesity Attenuates the Severity of the Obese Inflammatory Phenotype

Nutrients ◽

10.3390/nu13030757 ◽

2021 ◽

Vol 13 (3) ◽

pp. 757

Author(s):

Jennifer M. Monk ◽

Wenqing Wu ◽

Dion Lepp ◽

K. Peter Pauls ◽

Lindsay E. Robinson ◽

...

Keyword(s):

Weight Loss ◽

Control Diet ◽

Intestinal Health ◽

High Fat ◽

Navy Bean ◽

Fecal Microbiome ◽

Reduced Body ◽

Inflammatory Phenotype ◽

Obesogenic Diet ◽

Obese Phenotype

Cooked common beans (Phaseolus vulgaris) improve intestinal health in lean mice and attenuate intestinal dysbiosis and inflammation when consumed concurrent with obesity development. We determined the effects of a high-fat (HF) bean supplemented diet in mice with established obesity (induced by 12 weeks of HF diet (60% fat as kcal)) compared to obese mice consuming a HF or low-fat (LF) weight loss control diet. Obese C57BL/6 male mice remained consuming HF for eight weeks or were randomly switched from HF to an isocaloric HF with 15.7% cooked navy bean powder diet (HFàHFB) or LF (11% fat as kcal; HFàLF) (n = 12/group). HFàHFB improved the obese phenotype, including (i) fecal microbiome (increased Prevotella, Akkermansia muciniphila, and short-chain fatty acid levels), (ii) intestinal health (increased ZO-1, claudin-2, Muc2, Relmβ, and Reg3γ expression), and (iii) reduced adipose tissue (AT) inflammatory proteins (NFκBp65, STAT3, IL-6, MCP-1, and MIP-1α), versus HF (p < 0.05). Conversely, HFàLF reduced body weight and circulating hormones (leptin, resistin, and PAI-1) versus HF and HFàHFB (p < 0.05); however, AT inflammation and intestinal health markers were not improved to the same degree as HFàHFB (p < 0.05). Despite remaining on a HF obesogenic diet, introducing beans in established obesity improved the obese phenotype (intestinal health and adipose inflammation) more substantially than weight loss alone.

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Improved nutrient intake in older obese adults undergoing a structured diet and exercise intentional weight loss program

The journal of nutrition health & aging ◽

10.1007/s12603-010-0100-3 ◽

2010 ◽

Vol 14 (6) ◽

pp. 461-466 ◽

Cited By ~ 10

Author(s):

Gary D. Miller

Keyword(s):

Weight Loss ◽

Nutrient Intake ◽

Weight Loss Program ◽

Obese Adults ◽

Intentional Weight Loss ◽

Diet And Exercise

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Altered fibrin clot structure/function in patients with antiphospholipid syndrome: association with thrombotic manifestation

Thrombosis and Haemostasis ◽

10.1160/th13-11-0980 ◽

2014 ◽

Vol 112 (08) ◽

pp. 287-296 ◽

Cited By ~ 21

Author(s):

Magdalena Celińska-Löwenhoff ◽

Teresa Iwaniec ◽

Agnieszka Padjas ◽

Jacek Musiał ◽

Anetta Undas

Keyword(s):

Structure Function ◽

Antiphospholipid Syndrome ◽

Thrombotic Event ◽

Fibrin Clot ◽

Clot Lysis ◽

Lag Phase ◽

Lysis Time ◽

Clot Structure ◽

Clot Lysis Time ◽

D Dimer

SummaryWe tested the hypothesis that plasma fibrin clot structure/function is unfavourably altered in patients with antiphospholipid syndrome (APS). Ex vivo plasma clot permeability, turbidity and susceptibility to lysis were determined in 126 consecutive patients with APS enrolled five months or more since thrombotic event vs 105 controls. Patients with both primary and secondary APS were characterised by 11% lower clot permeability (p<0.001), 4.8% shorter lag phase (p<0.001), 10% longer clot lysis time (p<0.001), and 4.7% higher maximum level of D-dimer released from clots (p=0.02) as compared to the controls. Scanning electron microscopy images confirmed denser fibrin networks composed of thinner fibres in APS. Clots from patients with “triple-antibody positivity” were formed after shorter lag phase (p=0.019) and were lysed at a slower rate (p=0.004) than in the remainder. Clots from APS patients who experienced stroke and/or myocardial infarction were 8% less permeable (p=0.01) and susceptible to lysis (10.4% longer clot lysis time [p=0.006] and 4.5% slower release of D-dimer from clots [p=0.01]) compared with those following venous thromboembolism alone. Multivariate analysis adjusted for potential confounders showed that in APS patients, lupus anticoagulant and “triple-positivity” were the independent predictors of clot permeability, while “triple-positivity” predicted lysis time. We conclude that APS is associated with prothrombotic plasma fibrin clot phenotype, with more pronounced abnormalities in arterial thrombosis. Molecular background for this novel prothrombotic mechanism in APS remains to be established.

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Effects of weight loss via high fat vs. low fat alternate day fasting diets on free fatty acid profiles

Scientific Reports ◽

10.1038/srep07561 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 15

Author(s):

Krista A. Varady ◽

Vi T. Dam ◽

Monica C. Klempel ◽

Matthew Horne ◽

Rani Cruz ◽

...

Keyword(s):

Weight Loss ◽

Fatty Acid ◽

Free Fatty Acid ◽

Fatty Acid Profiles ◽

High Fat ◽

Low Fat ◽

Alternate Day Fasting

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Frequent intentional weight loss is associated with higher ghrelin and lower glucose and androgen levels in postmenopausal women

Nutrition Research ◽

10.1016/j.nutres.2010.02.002 ◽

2010 ◽

Vol 30 (3) ◽

pp. 163-170 ◽

Cited By ~ 22

Author(s):

Laura E. Hooper ◽

Karen E. Foster-Schubert ◽

David S. Weigle ◽

Bess Sorensen ◽

Cornelia M. Ulrich ◽

...

Keyword(s):

Weight Loss ◽

Postmenopausal Women ◽

Intentional Weight Loss ◽

Lower Glucose ◽

Androgen Levels

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Plasma fibrin clot properties in the G20210A prothrombin mutation carriers following venous thromboembolism: the effect of rivaroxaban

Thrombosis and Haemostasis ◽

10.1160/th17-01-0060 ◽

2017 ◽

Vol 117 (09) ◽

pp. 1739-1749 ◽

Cited By ~ 8

Author(s):

Agnieszka Janion-Sadowska ◽

Joanna Natorska ◽

Jakub Siudut ◽

Michal Zabczyk ◽

Andrzej Stanisz ◽

...

Keyword(s):

Venous Thromboembolism ◽

Fibrin Clot ◽

Clot Lysis ◽

Mutation Carriers ◽

Lysis Time ◽

Prothrombin Mutation ◽

Fibrinolysis Inhibitor ◽

Heterozygous Carriers ◽

Mutation Group ◽

Clot Structure

SummaryWe sought to investigate whether the G20210A prothrombin mutation modifies plasma fibrin clot properties in patients after venous thromboembolism (VTE) and how rivaroxaban treatment affects these alterations. We studied 34 prothrombin mutation heterozygous carriers and sex- and age-matched 34 non-carriers, all at least three months since the first VTE episode, before and during treatment with rivaroxaban. Clot permeability (Ks) and clot lysis time (CLT) with or without elimination of thrombin activatable fibrinolysis inhibitor (TAFI) were assessed at baseline, 2–6 hours (h) after and 20–25 h after intake of rivaroxaban (20 mg/day). At baseline, the prothrombin mutation group formed denser clots (Ks −12 %, p=0.0006) and had impaired fibrinolysis (CLT +14 %, p=0.004, and CLT-TAFI +13 %, p=0.03) compared with the no mutation group and were similar to those observed in 15 healthy unrelated prothrombin mutation carriers. The G20210A prothrombin mutation was the independent predictor for Ks and CLT before rivaroxaban intake. At 2–6 h after rivaroxaban intake, clot properties improved in both G20210A carriers and non-carriers (Ks +38 %, and +37 %, CLT −25 % and −25 %, CLT-TAFI −20 % and −24 %, respectively, all p<0.001), but those parameters were worse in the prothrombin mutation group (Ks −12.8 %, CLT +17 %, CLT-TAFI +13 %, all p<0.001). Rivaroxaban concentration correlated with fibrin clot properties. After 20–25 h since rivaroxaban intake most clot properties returned to baseline. Rivaroxaban-related differences in clot structure were confirmed by scanning electron microscopy images. In conclusion, rivaroxaban treatment, though improves fibrin clot properties, cannot abolish more prothrombotic fibrin clot phenotype observed in prothrombin mutation carriers following VTE.

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