Short summary

The PhD project investigates the association between intentional weight loss and thrombotic risk markers after a high-fat meal. Patients admitted to a gastric bypass surgery are used as a model of intentional weight loss. Intentional weight loss is associated with unknown harmful effects in overweight individuals, and this study investigates possible mechanisms in blood samples underlying the harmful effects of intentional weight loss.

Rationale

For 25 years, studies have shown that intentional weight loss is associated with unknown harmful effects leading to increased morbidity and mortality in spite of a beneficial impact on several disease risk markers. Thus, unknown harmful effects may exceed the beneficial effects under certain circumstances, but the mechanisms are still unknown.

Cardiovascular disease is a major cause of morbidity and mortality and is often caused by atherothrombosis. Thrombus formation is caused by disturbances in the haemostatic balance with enhanced coagulation activation. We and others have reported postprandial activation of blood coagulation factor VII (FVII) after a high-fat meal, and not after a low-fat meal, and postprandial coagulation activation might be "the missing link" between intentional weight loss and mortality risk, since people spend most of their lives in the non-fasting state. The link between intentional weight loss and thrombotic risk has been poorly investigated.

Postprandial coagulation activation is usually not accompanied by increased thrombin generation, but rather a decrease in prothrombin fragment 1+2 (F1+2) in healthy normal weight individuals and in patients with coronary artery disease. Most likely, the concentration of tissue factor (TF) is not high enough to support co-factor activity for FVIIa in the generation of thrombin. However, we observed a postprandial increase in F1+2 in a weight loss maintenance study in overweight individuals, where participants lost >8% of their body weight during 8 weeks before study start. Overweight combined with a negative energy balance might cause a stress situation triggering postprandial thrombin generation, tentatively indicating that thrombin generation is related to metabolic disturbances associated with the catabolic state during weight loss.

Interestingly, it was recently shown that high-fat meals (but not low-fat meals) promote intestinal absorption of lipopolysaccharides (LPS) from the gut microbiota (bacteria), and as a consequence postprandial concentrations of endotoxins in blood are increased. Endotoxins stimulate the expression of TF on blood monocytes, thereby activating coagulation via FVIIa. Also, endotoxin infusion increases thrombin generation (F1+2) after an intravenous fat emulsion in healthy men. Postprandial endotoxemia is more pronounced in obese than in normal weight individuals after a high-fat meal, perhaps due to differences in the gut microbiota composition. Thrombin generation might therefore increase after a high-fat meal in obese individuals, further reinforced by leptin from adipose tissue, which also increases TF expression on monocytes.

Further, during weight loss and negative energy balance, inflammatory acute phase proteins might be increased, and the cytokine interleukin 6 (IL-6) is an important intermediate factor in TF expression during low-grade endotoxemia. Such a stress situation may potentially further increase the postprandial thrombin generation associated with high-fat meals.

People who undergo bariatric surgery must achieve a lifestyle induced weight loss of 8% of total body weight within three months before the operation. The purpose is to reduce the liver fat content, thereby increasing the intra-abdominal space thus facilitating the operation. The operation results in a rapid weight loss averaging 70% of the overweight. Thus, this group of patients is an appropriate model to study effects of a rapid weight loss induced by lifestyle followed by bariatric surgery.

The purpose of the study is to investigate potential mechanisms underlying the harmful effects of intentional weight. The study objective is to investigate if obesity in itself or rapid weight loss induced by lifestyle or bariatric surgery is associated with postprandial thrombin generation after a high-fat meal compared to a low-fat meal.  

Description of the cohort

The cohort is patients admitted to a gastric bypass (bariatric patients) at the Section of Endocrinology, Hospital of South West Jutland. Bariatric patients:

• Women and men
• 18-65 years
• BMI (above 35 kg/m²)
• Diabetic (above 50 %) and non-diabetic
• Not postmenopausal
• Not previously diagnosed with cancer disorders, liver disorders or haematological disorders.
• Not treated with anticoagulants 

Data and biological material

There are 6 meal test days, which correspond to two types of meals (low-fat meal and high-fat meal) consumed at three different treatment periods such as 1): before weight loss 2): after lifestyle-induced weight loss and 3): after gastric bypass.

Following types of data are collected during clinical trials:

• Date of clinical trials
• Blood samples
• Stool samples
• Patient information (medical diagnosis and treatment)
• Age, Sex, BMI (body weight /body height), smoker/non-smoker
• Meal/liquid intake

Collaborating researchers and departments

Unit for Thrombosis Research
Department of Clinical Biochemistry, Hospital of South West Jutland.
Department of Regional Health Research, University of Southern Denmark

• PhD student Line Espenhain Andersen, MSc 

Unit for Thrombosis Research
Department of Clinical Biochemistry, Hospital of South West Jutland.
Department of Regional Health Research, University of Southern Denmark

• Associate Professor Else-Marie Bladbjerg, MSc, PhD

Obesity Research
Section of Endocrinology, Department of Medicine, Hospital of South West Jutland
Department of Regional Health Research, University of Southern Denmark

• Associate professor and senior physician Claus Bogh Juhl, MD, PhD

Focused Research Unit for Molecular Diagnostic and Clinical Research
Hospital of Southern Denmark
Department of Regional Health Research, University of Southern Denmark

• Clinical Professor and senior physician Vibeke Andersen, MD, PhD