Introduction: Obesity is approaching epidemic status in the United States and is strongly associated with a higher risk of heart failure after myocardial infarction (MI), a major cause of morbidity and mortality in obese individuals. However, the mechanisms underlying obesity-associated heart failure are poorly understood. Lysophosphatidic acid (LPA), produced by autotaxin (ATX), is highly expressed in adipose tissue with increased levels in obesity and has been shown to mediate post-MI inflammation. Methods: 3-week aged male C57BL/6J mice were randomly assigned to low-fat (LFD-10%) or high-fat (HFD-60%) diet based on the percentage of calories from fat. HFD-fed mice were randomly assigned to receive the specific ATX inhibitor, PF-8380 at 10 mg/kg twice daily. 2 months after initiating the diet, mice were randomized to undergo MI surgery (permanent ligation of the left anterior descending artery) or sham surgery. Results: MI was associated with an increased number of circulating inflammatory monocytes (CD45 + /Ly6C + /CD115 + ), as well as cardiac total and pro-inflammatory macrophages (CD45 + /F4-80 + /CD11b + /CD86 + ), as assessed by flow cytometry (Fig. 1A). This effect was exacerbated in HFD-fed mice but significantly attenuated in HFD+PF8380 treated mice with effective ATX inhibition. Changes in circulating and cardiac immune cells were reflective of increased proliferation of bone marrow progenitors, a phenomenon that was blunted by ATX inhibition (Fig. 1B). Moreover, HFD was associated with larger scar size (Fig. 1C) and worse cardiac functional recovery (Fig. 1D) 30 days after MI. The obesity-asscoiated heart failure could be rescued by ATX inhibition. Conclusion: ATX/LPA plays an important role in modulating inflammation and could be a therapeutic target for obesity-related coronary heart diseases.