Research Projects

The chief contributors to obesity induced adipose tissue maladaptive response are inflammation and fibrosis. A previous study by our lab comparing the adipose tissue of obese and non-obese individuals had revealed several differentially regulated genes. Among them F2RL3 (Coagulation Factor II (Thrombin) Receptor) protein was found to be elevated in obese, which could be a potential target to alleviate both fibrosis and inflammation in adipose tissue. It is activated by key effector proteases of coagulation and inflammatory pathways. F2RL3/PAR-4 expression is heightened in response to stimuli associated with coagulation and inflammation like thrombin, sphingosine-1-phosphate (S1P), IL-1α, TNFα and hyperglycemia suggesting it as a sensor of pathological stress. It has been established that in obesity there exist a hypercoagulable state with increased levels of prothrombotic molecules such as Thrombin, an activator of F2RL3/ PAR4. Also, there is pro-inflammatory state with immune effectors such as Cathepsin G activating F2RL3. A recent study on diabetic mice has shown that abundance of F2RL3 expression in cardiomyocytes drives NLRP3 inflammasome activation with enhanced secretion of IL-1β; a known causative agent of insulin resistance. Studies have also implicated NLRP3 Inflammasome in the development of adipose tissue inflammation and fibrosis. Based on the above knowledge and to reinforce missing links between obesity and its co-morbidities, we hypothesise that the presence of elevated levels of pro-inflammatory and pro-thrombotic molecules such as S1P, IL1α in obesity upregulates F2RL3 expression in adipocytes leading to activation of NLRP3 inflammasome. NLRP3 then triggers expression of fibrotic and inflammatory molecules leading to adipose tissue dysfunctions. NLRP3 also enhances IL-1β production which contributes to insulin resistance. In our study we will first compare expression of F2RL3and its influencers between obese and non-obese individuals. Further to establish whether F2RL3 activation leads to adipose tissue derangement through its action on NLRP3 inflammasome activation, we will use activators of this receptor in adipocyte cell cultures and observe changes in the expression of inflammasome and fibrosis genes. Finally, we will investigate if BMS-986120 (a clinically approved antiplatelet drug) can successfully block the action of proteases from activating F2RL3 receptor and rescue it from malfunction. Upon successful completion of our study, we will gain novel insight into the role of F2RL3 activation in obese individuals and whether it transduces the inflammatory signals through NLRP3 activation in adipocytes. Such a revelation has not been documented so far. Modulation of F2RL3 in obese adipocytes will be instrumental in bringing novel insights into its role in progression to insulin resistance. Finally, F2RL3 blockade using BMS-986120 will reveal its beneficial potential in ameliorating the co-morbidities of obesity.