The crucial roles of coagulation factors in inducing brown adipose tissue dysfunction and systemic metabolic disorder in obesity

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Hayashi ◽  
I Shimizu ◽  
Y Yoshida ◽  
G Katsuumi ◽  
M Suda ◽  
...  
Keyword(s):  
Glucose Intolerance ◽  
Metabolic Disorders ◽  
Metabolic Stress ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Mitochondrial Ros ◽  
Brown Adipose ◽  
Thermogenic Response

Abstract   The prevalence of obesity is increasing worldwide. Obese individuals are predisposed to cardio-metabolic disorders. Brown adipose tissue (BAT) is an active metabolic organ abundant with mitochondria, and studies suggest a potential role of BAT in the maintenance of metabolic health in rodents and humans. Metabolic stress causes BAT dysfunction, but the underlying mechanisms are largely unknown. Coagulation factor Xa (FXa) is critically involved in a coagulation cascade, and it is also known to mediate biological effects by the activation of protease-activated receptor (PAR)-signaling. Accumulating evidence shows that PAR1 contributes to tissue remodeling in cardiovascular system. Analyzing deposited microarray data, we found transcripts for coagulation factors including factor VII (F7), factor X (F10), and PAR1 receptor were increased in BAT from obese mice. Here we show a previously unknown role of FXa-PAR signaling in promoting BAT dysfunction and systemic metabolic disorder in a murine dietary obese model. Imposing a high fat diet (HFD) on C57BL/6NCr mice led to a marked increase in tissue factor (TF), coagulation factor VII and FXa in BAT. TF-FVIIa (activated form of FVII)-FXa complex is known to activate PAR1, and we found a significant increase in PAR1 expression in BAT upon metabolic stress. Administration of a FXa inhibitor ameliorated BAT whitening, improved thermogenic response and systemic glucose intolerance upon dietary obesity. Fxa inhibition reduced reactive oxygen species (ROS) level in BAT. In contrast, administration of warfarin did not show any phenotype in BAT. BAT specific TF and PAR1 over-expression model showed significant whitening of this tissue, which was associated with systemic glucose intolerance. We generated BAT specific PAR1 KO mice. BAT-PAR1 KO mice exhibited re-browning of BAT along with reduced ROS level in this tissue. In BAT-PAR1 KO mice, glucose intolerance and thermogenic response under a metabolically stressed condition were ameliorated. In differentiated brown adipocytes, FXa markedly increased mitochondrial ROS and reduced mitochondrial membrane potential. Inhibition of PAR1 ameliorated FXa-induced mitochondrial ROS production and reduction in membrane potential. We also found that plasma FXa level did not increase in obese mice as well as in obese individuals. These results suggest the previously unknown role of coagulation systems in promoting BAT dysfunction, leading to systemic metabolic disorders. Maintenance of BAT homeostasis through the suppression of FXa-PAR1 signaling would become a new therapeutic target for obesity and diabetes. Funding Acknowledgement Type of funding source: None

3308The critical roles of coagulation factors in inducing brown adipose tissue dysfunction and systemic metabolic disorder in obesity

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Hayashi ◽  
I S Shimizu ◽  
Y Y Yoshida ◽  
R I Ikegami ◽  
G K Katsuumi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Membrane Potential ◽  
Glucose Intolerance ◽  
Metabolic Disorder ◽  
Metabolic Disorders ◽  
Metabolic Stress ◽  
Coagulation Factor ◽  
Brown Adipose ◽  
Thermogenic Response

Abstract Obese individuals are predisposed to cardio-metabolic disorders. Brown adipose tissue (BAT) is an active metabolic organ abundant with mitochondria, and studies suggest a potential role of BAT in the maintenance of metabolic health in rodents and humans. Metabolic stress causes BAT dysfunction, but the underlying mechanisms are largely unknown. Coagulation factor Xa (FXa) is critically involved in a coagulation cascade, and it is also known to mediate biological effects by the activation of protease-activated receptor (PAR)-signaling. Accumulating evidence shows that PAR1 contributes to tissue remodeling in cardiovascular system. Here we show a previously unknown role of FXa-PAR signaling in promoting BAT dysfunction and systemic metabolic disorder in a murine dietary obese model. Imposing a high fat diet (HFD) on C57BL/6NCr mice led to a marked increase in tissue factor (TF), coagulation factor VII and FXa in BAT. TF-FVIIa (activated form of FVII)-FXa complex is known to activate PAR1, and we found a significant increase in PAR1 expression in BAT upon metabolic stress. Administration of a FXa inhibitor ameliorated BAT whitening, improved thermogenic response and systemic glucose intolerance upon dietary obesity. In contrast, administration of warfarin did not show any phenotype in BAT. BAT specific TF and PAR1 over-expression model showed significant whitening of this tissue, which was associated with systemic glucose intolerance. BAT specific PAR1 KO mice improved glucose intolerance and thermogenic response under a metabolically stressed condition. In differentiated brown adipocytes, FXa markedly increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial membrane potential. Inhibition of PAR1 ameliorated FXa-induced mitochondrial ROS production and reduction in membrane potential. We also found that plasma FXa level did not increase in obese mice as well as in obese individuals. These results suggest the previously unknown role of coagulation systems in promoting BAT dysfunction, leading to systemic metabolic disorders. Maintenance of BAT homeostasis through the suppression of FXa-PAR1 signaling would become a new therapeutic target for obesity and diabetes.

Sources of Variability in Coagulation Factor Assays

1987 ◽  
Vol 58 (04) ◽  
pp. 1073-1077 ◽  
Author(s):  
S G Thompson ◽  
J C Martin ◽  
T W Meade
Keyword(s):  
Total Variation ◽  
Antithrombin Iii ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Arterial Disease ◽  
Factor Vii ◽  
Small Component ◽  
Future Studies ◽  
Two Measures

SummaryEstimates of the components of variation of a number of coagulation factor assays are presented and are compared with those for other haematological and biochemical variables. They have been derived from a study in which fourteen volunteers gave blood samples approximately bi-monthly for three years. The systematic between-batch variation w7as generally only a small component of the total variation. However, the proportion of the total variation due to differences between people ranged from about 15% in the case of two measures of antithrombin III to about 85% for cholesterol and haemoglobin. For factor VII activity and fibrinogen, the figure was just over 70%. These estimates of the components of variation are not generally available in the literature. In view of the increasing interest in the role of coagulation factors in the pathogenesis of arterial disease, estimates of this kind are needed both for the interpretation of observed relationships as well as for planning sample sizes for future studies.

scholarly journals SAT-LB107 Insulin Sensing by Astrocytes Is Critical for Normal Thermogenesis and Body Temperature Regulation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jennifer Wootton Hill ◽  
Iyad H Manaserh
Keyword(s):  
Body Temperature ◽  
Energy Expenditure ◽  
Insulin Signaling ◽  
Insulin Receptors ◽  
Normal Body Temperature ◽  
Metabolic Dysregulation ◽  
Brown Adipose ◽  
Novel Target ◽  
Thermogenic Response

Abstract The important role of astrocytes in the central control of energy balance and glucose homeostasis has only recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (IR) in astrocytes (IRKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IRKOGFAP mice displayed a significant decrease in energy expenditure and a striking decrease in basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. Brown adipose tissue in IRKOGFAP mice exhibited increased adipocyte size, more apoptosis, loss of innervation, and decreased βAR3 expression levels. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

Coagulation factor levels in neurosurgical patients with mild prolongation of prothrombin time: effect on plasma transfusion therapy

2011 ◽  
Vol 114 (1) ◽  
pp. 3-7 ◽  
Author(s):  
Karén Matevosyan ◽  
Christopher Madden ◽  
Samuel L. Barnett ◽  
Joseph E. Beshay ◽  
Cynthia Rutherford ◽  
...  
Keyword(s):  
Prothrombin Time ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Scientific Data ◽  
Factor Vii ◽  
Plasma Transfusion ◽  
Transfusion Therapy ◽  
Study Results ◽  
Neurosurgical Patients ◽  
Transfusion Guidelines

Object Neurosurgical patients often have mildly prolonged prothrombin time (PT) or international normalized ratio (INR). In the absence of liver disease this mild prolongation appears to be due to the use of very sensitive PT reagents. Therefore, the authors performed relevant coagulation factor assays to assess coagulopathy in such patients. They also compared plasma transfusion practices in their hospital before and after the study. Methods The authors tested 30 plasma specimens from 25 patients with an INR of 1.3–1.7 for coagulation factors II, VII, and VIII. They also evaluated plasma orders during the 5-month study period and compared them with similar poststudy periods following changes in plasma transfusion guidelines based on the study results. Results At the time of plasma orders the median INR was 1.35 (range 1.3–1.7, normal reference range 0.9–1.2) with a corresponding median PT of 13.6 seconds (range 12.8–17.6 seconds). All partial thromboplastin times were normal (median 29.0 seconds, range 19.3–33.7 seconds). The median factor VII level was 57% (range 25%–124%), whereas the hemostatic levels recommended for major surgery are 15%–25%. Factors II and VIII levels were also within the hemostatic range (median 72% and 118%, respectively). Based on these scientific data, plasma transfusion guidelines were modified and resulted in a 75%–85% reduction in plasma orders for mildly prolonged INR over the next 2 years. Conclusions Neurosurgical patients with a mild prolongation of INR (up to 1.7) have hemostatically normal levels of important coagulation factors, and the authors recommend that plasma not be transfused to simply correct this abnormal laboratory value.

scholarly journals The role of leukocytes in thrombosis

Blood ◽  
2016 ◽  
Vol 128 (6) ◽  
pp. 753-762 ◽  
Author(s):  
Laura L. Swystun ◽  
Patricia C. Liaw
Keyword(s):  
Platelet Activation ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Immune Functions ◽  
Hemostatic System ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
New Evidence

AbstractIn recent years, the traditional view of the hemostatic system as being regulated by a coagulation factor cascade coupled with platelet activation has been increasingly challenged by new evidence that activation of the immune system strongly influences blood coagulation and pathological thrombus formation. Leukocytes can be induced to express tissue factor and release proinflammatory and procoagulant molecules such as granular enzymes, cytokines, and damage-associated molecular patterns. These mediators can influence all aspects of thrombus formation, including platelet activation and adhesion, and activation of the intrinsic and extrinsic coagulation pathways. Leukocyte-released procoagulant mediators increase systemic thrombogenicity, and leukocytes are actively recruited to the site of thrombus formation through interactions with platelets and endothelial cell adhesion molecules. Additionally, phagocytic leukocytes are involved in fibrinolysis and thrombus resolution, and can regulate clearance of platelets and coagulation factors. Dysregulated activation of leukocyte innate immune functions thus plays a role in pathological thrombus formation. Modulation of the interactions between leukocytes or leukocyte-derived procoagulant materials and the traditional hemostatic system is an attractive target for the development of novel antithrombotic strategies.

scholarly journals The Essential Role of PRAK in Preserving Cardiac Function and Insulin Resistance in High-Fat Diet-Induced Diabetes

2021 ◽  
Vol 22 (15) ◽  
pp. 7995
Author(s):  
Jianfeng Du ◽  
Yu Tina Zhao ◽  
Hao Wang ◽  
Ling X. Zhang ◽  
Gangjian Qin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiac Function ◽  
Western Blot ◽  
Glucose Intolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Wild Type ◽  
High Fat

Regulated/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK−/− mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPKα, ERK-44/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and βMHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPKα, and ERK44/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.

scholarly journals Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a Large Cohort of Patients—A Single-Center Experience in Genetic Diagnosis

2021 ◽  
Vol 10 (2) ◽  
pp. 347
Author(s):  
Barbara Preisler ◽  
Behnaz Pezeshkpoor ◽  
Atanas Banchev ◽  
Ronald Fischer ◽  
Barbara Zieger ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Single Gene ◽  
Genetic Defect ◽  
Genetic Diagnosis ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Molecular Genetic Analysis ◽  
Factor Vii ◽  
Factor Xii ◽  
Activity Levels

Background: Familial multiple coagulation factor deficiencies (FMCFDs) are a group of inherited hemostatic disorders with the simultaneous reduction of plasma activity of at least two coagulation factors. As consequence, the type and severity of symptoms and the management of bleeding/thrombotic episodes vary among patients. The aim of this study was to identify the underlying genetic defect in patients with FMCFDs. Methods: Activity levels were collected from the largest cohort of laboratory-diagnosed FMCFD patients described so far. Genetic analysis was performed using next-generation sequencing. Results: In total, 52 FMCFDs resulted from coincidental co-inheritance of single-factor deficiencies. All coagulation factors (except factor XII (FXII)) were involved in different combinations. Factor VII (FVII) deficiency showed the highest prevalence. The second group summarized 21 patients with FMCFDs due to a single-gene defect resulting in combined FV/FVIII deficiency or vitamin K–dependent coagulation factor deficiency. In the third group, nine patients with a combined deficiency of FVII and FX caused by the partial deletion of chromosome 13 were identified. The majority of patients exhibited bleeding symptoms while thrombotic events were uncommon. Conclusions: FMCFDs are heritable abnormalities of hemostasis with a very low population frequency rendering them orphan diseases. A combination of comprehensive screening of residual activities and molecular genetic analysis could avoid under- and misdiagnosis.

scholarly journals Deficiency of coagulation factor Vll in a 4 years old child with 13q deletion syndrome: a case report

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Housam AL Madani ◽  
Soltan Hassan ◽  
Ghada Ajwa ◽  
Basel Dahlawi
Keyword(s):  
Case Report ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Deletion Syndrome ◽  
Bleeding Disorders ◽  
Chromosome 13 ◽  
Factor Vii Deficiency ◽  
13Q Deletion ◽  
Congenital Factor

Background: Factor VII deficiency is rare inherited bleeding disorders, have been identified in the Factor VII gene located on chromosome 13 with very few cases reported. Factor VII deficiency was first described by Alexander et al. in 1951.The disorder has also been known as Alexander's disease. It is the rare inherited bleeding disorders’ with an estimated incidence of 1 case per 3,00,000 to 5,00,000 individuals. Objective and method: We did a case report and literature review for deficiency of coagulation factors VII was found in a 4 years patient who had chromosomal aberration 13q deletion syndrome (46, XX, del 13q32-13q33). This loci involved in synthesis or constitution of factor VII. Results: A review of the gene map of chromosome 13 indicated that Factors VII and X are coded on the long arm of chromosome 13, within the deleted region. Conclusion: Congenital Factor VII deficiency is a rare cause of bleeding disorder, which should be suspected in a bleeding child presenting in infancy when platelets and aPTT are normal with abnormal PT. Congenital Factor VII deficiency association with 46, XX, del (13q32– 13q33) syndrome is very rare disorder and further cases should be reported to know the outcome and the risk of complication in such a cases.

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