Abstract Fri036: Infiltration Of Neutrophils To Adipose Tissue Aggravate Insulin Resistance Following Myocardial Infarction In Obesity

Background: Undiagnosed insulin resistance (IR) is prevalent among non-diabetic patients with acute myocardial infarction (MI) and is linked to a worse prognosis. The underlying mechanisms remain unclear, but post-MI inflammation is a likely contributor. This study hypothesizes that injury-exposed neutrophils infiltrate white adipose tissue (WAT), triggering chronic inflammation and IR, ultimately contributing to heart failure. Methods: Lean and high-fat diet (HFD)-induced obese mice underwent permanent ligation of the left anterior descending (LAD) artery to induce MI. Insulin resistance was assessed using hyperinsulinemic-euglycemic clamp (HIEG) studies and intraperitoneal glucose tolerance tests (IPGTT). Myeloid cell-specific gene deletions were performed using bone marrow transplantation (BMT). Leukocyte profiling, systemic cytokine analysis, histological examinations, and cardiac function assessments were conducted using flow cytometry, immunohistochemistry (IHC), and echocardiography, respectively. In vitro co-culture studies with 3T3-L1 adipocytes and bone marrow-derived macrophages (BMDMs) were also performed. Results: In lean mice, MI induced a systemic inflammatory response and enhanced bone marrow myelopoiesis within 24 hours post-MI. Despite heightened inflammation, IR was not observed; instead, insulin sensitivity increased within the first week. A similar response was noted in obese mice, likely due to significant weight loss and adipose tissue beiging via sympathetic nervous system activation. However, obese mice exhibited progressive IR starting at 7 weeks post-MI, persisting for 6 months. This delayed IR was associated with adipocyte stem cell fibroblastic transitions, driven by neutrophil infiltration into WAT. Neutrophil-macrophage interactions triggered NETosis and the release of S100A8/A9, a TLR4 ligand and NLRP3 inflammasome activator, promoting the expansion of pro-inflammatory CCR2^hiCX3CR1^hi macrophages linked to IR. These findings were validated in vitro and in vivo using BMT models. Deleting S100a8/a9 or Nlrp3 reduced neutrophilia, decreased macrophage-driven inflammation, and improved IR. Conclusions: Overall, this study suggests that neutrophil infiltration into WAT post-MI drives IR in obesity, while lean mice remain unaffected. Targeting neutrophil-macrophage interactions and S100A8/A9 signaling may offer novel therapeutic strategies to mitigate IR and improve post-MI metabolic outcomes, particularly in obese patients.