State of the art
Obesity is one of the major health problems in the world; the WHO estimates that in 2016 39% of men and women aged 18+ were overweight (body mass index; 25 ≤ BMI < 30 kg/m2) and 11% of men and 15% of women were obese (BMI ≥ 30 kg/m2). Excessive and i.e. abnormal ectopic (i.e. visceral) fat accumulation presents one of the major risk factors for thrombotic disorders, such as cardiovascular disease, stroke, and venous thromboembolism due to the associated cluster of pathogenic factors comprising adipose tissue-derived low-grade chronic inflammation (e.g. CRP, IL-6, TNF-α), insulin resistance and oxidative stress (e.g. lipid peroxidation). Platelet hyper-reactivity plays a central role in accelerating thrombotic events in obesity (BMI over 30 kg/m2). For example, loss of platelet inhibition by insulin has been suggested as a major determinant of platelet hyperactivity in obese patients. It is known that insulin inhibits splicing of tissue factor (TF) pre-mRNA in platelets; diabetic complications of obesity may therefore contribute independently to the thrombogenicity of the platelets and atherothrombosis. Furthermore, obese adolescents have significantly increased Mean Platelet Volume (MPV) as compared to their healthy peers, indicating broader changes in platelet phenotypes.
We hypothesize that diabetic complications of obesity produce distinct change in platelet transcriptomes that can be used as risk indicator for cardiovascular events. We propose to bridge basic mechanistic and epidemiological approaches to define platelet transcriptome changes distinguishing obese individuals with metabolic complications from obese as well as normal weight individuals.