SUN-696 Thrombospondin-1 in Severe Obesity: a Hypoxia-Suppressed Cardiometabolic Biomarker Interacting with Endothelin-1

Abstract Disclosure: M. Mirabelli: None. M. Greco: None. F.S. Brunetti: None. E. Chiefari: None. D.P. Foti: None. A. Brunetti: None. Background: Thrombospondin-1 (TSP1) is a multimeric glycoprotein mainly stored in platelet (PLT) granules but also secreted by various cell types, contributing to metabolic, inflammatory, and thrombotic processes. Although TSP1 has been linked to adipose tissue dysfunction and insulin resistance (IR), its precise role in obesity remains unclear. Endothelin-1 (ET1), a potent vasoconstrictor, interacts with TSP1 for receptor binding and may underlie the heightened cardiometabolic risks observed in obesity. This study investigates the association between the severity of obesity and circulating levels of TSP1 and ET1, as well as their potential implications in obesity-related pathophysiology. Methods: The study enrolled 58 nondiabetic obese individuals (median age: 37 years, predominantly female) without established cardiovascular disease. Anthropometric, clinical, metabolic, inflammatory, and hemato-coagulative parameters were measured, with serum TSP1 and ET1 levels assessed using automated ELISA. Participants were stratified into two groups based on BMI (<35 vs. ≥35 kg/m²). Correlations between TSP1, ET1, and other laboratory markers were analyzed. Results: The median BMI was 33.8 kg/m², with 46% of participants classified as severely obese. IR was prevalent in 69.6% of participants. TSP1 and ET1 levels tended to be lower in those with severe obesity. TSP1 correlated positively with white blood cell count (r = 0.360, p < 0.01), PLT (r = 0.403, p < 0.01), and HbA1c (r = 0.373, p < 0.01), highlighting its involvement in both inflammatory and glycemic control pathways. In contrast, ET1 exhibited positive correlations with liver enzymes and triglycerides, while being negatively correlated with PLT and D-dimer. Severe obesity was associated with higher IR indices, elevated D-dimer, and increased inflammatory markers, alongside a decreased TSP1-to-PLT ratio (89.56 vs. 118.33, p = 0.022)—an index created to account for platelet activation. Further supporting the link to visceral adipose tissue, in vitro 3T3-L1 adipocyte experiments under hypoxic conditions, simulating the microenvironment of enlarged visceral fat, revealed reduced TSP1 transcription and secretion. Conclusions: Severe obesity is characterized by reduced circulating levels of TSP1 and ET1, which display distinct relationships with metabolic, inflammatory, and thrombotic parameters. The hypoxia-induced decrease in TSP1, associated with expanded visceral fat, along with the concurrent reduction in circulating ET1, may serve as compensatory mechanisms to mitigate vascular dysfunction in severe obesity. TSP1 emerges as a promising biomarker for cardiometabolic risk in obesity, meriting further investigation into its therapeutic potential for preventing obesity-related complications. Presentation: Sunday, July 13, 2025