Unraveling Fatty Acid-driven Mechanisms of Platelet Hyper-Activation in Obesity

PROJECT SUMMARY
Obesity is a serious health concern in the United States, affecting 41.9% of the population and resulting in an
estimated annual medical cost of nearly $179 billion. Notably, obesity increases the risk of cardiovascular
diseases due to inflammation and thrombotic events. Individuals with obesity often exhibit hyper-reactive
platelets and reduced sensitivity to anti-platelet therapy, yet the mechanisms driving these altered platelet
phenotypes remain poorly understood, representing a significant knowledge gap in platelet biology. Our
preliminary data reveal that platelets from obese mice exhibit an altered lipidome that corresponds with enhanced
reactivity. Further, we previously demonstrated that platelet-generating cells, megakaryocytes (MKs), can
effectively incorporate fatty acids into their membrane, both in vivo and in vitro. However, it is unknown if and how
this uptake directly translates into alterations in platelet membrane composition in disease. As such, our central
hypothesis is that the hyper-reactive platelet phenotype observed in obesity arises from the increased
incorporation of dietary saturated fatty acids (SFAs) into platelet membranes, leading to a higher membrane lipid
saturation that in turn enhances receptor accumulation within lipid rafts, ultimately augmenting platelet reactivity.
To test this hypothesis, Aim 1 will unravel how fatty acid uptake influences platelet membrane composition.
Through in vitro experiments and in vivo studies utilizing high-fat diets with varying SFA concentrations, I aim to
determine whether platelets acquire fatty acids from both MKs and the plasma. Aim 2 will test the influence of
dietary SFAs on platelet reactivity and thrombus formation. By conducting in vivo studies with escalating SFA
content in diets, I will establish a direct link between dietary factors and altered platelet phenotypes. Aim 3 will
investigate whether dietary SFA-induced platelet hyper-reactivity is caused by changes in lipid raft content and
subsequent receptor signaling. My investigations will include characterizing lipid raft density and receptor
content, as well as analyzing the effects on downstream signaling both in vitro and in vivo. Overall, this proposal
aims to uncover the precise mechanisms by which dietary SFAs are integrated into platelet membranes and how
this integration influences platelet function. The main aims of this proposal are the identification of new avenues
for pharmacological interventions targeting lipid receptors in platelets or of novel dietary modifications for obese
individuals, ultimately contributing to a better management of obesity-related cardiovascular complications.

Grant Number: 5K99HL175037-02
NIH Institute/Center: NIH
Principal Investigator: Maria Barrachina