Abstract Body: Systemic insulin resistance (IR), a hallmark of prediabetes and type 2 diabetes, accelerates atherosclerotic cardiovascular disease; however, how systemic IR reshapes arterial smooth muscle cell (SMC) phenotypes within lesions remains unclear. We tested the hypothesis that systemic IR reprograms distinct arterial SMC populations toward inflammatory states during atherosclerosis. To induce systemic IR, 8-week-old Ldlr^-/- mice were fed a high-fat, high-sucrose, cholesterol-enriched diet for 12 weeks and then treated with vehicle (saline/DMSO) or the insulin receptor antagonist S961 (0.57 mg/kg/day) via osmotic minipumps for an additional 6 weeks (n=12/group). S961 induced marked hyperglycemia (490 ± 21 vs 175 ± 6 mg/dL; p=7.4×10^-7) and hyperinsulinemia (p=7.4×10^-7) as compared with the vehicle control, with glucose and insulin tolerance tests confirming severe IR (p<0.001). S961-treated mice exhibited lipemic plasma with elevated triglycerides (885 ± 77 vs 270 ± 54 mg/dL; p=2.2×10^-5) and cholesterol (698 ± 88 vs 324 ± 47 mg/dL; p=0.0035). Lipoprotein profiles revealed increased triglyceride-rich lipoprotein (TRL) particles with enrichment of TRL triglycerides, cholesterol and apolipoprotein B (APOB) (all p<0.05). Plasma APOB levels were also increased (10.8 ± 2.0 vs 5.8 ± 1.3 mg/mL; p=0.033), with an 18.2% reduction in fractional clearance rate (p=0.045) and no difference in production rate as assessed by targeted mass spectrometry after ¹³C¹⁵N-lysine injection. Quantification of atherosclerosis across the aortic root revealed larger lesion areas in S961-treated mice compared to controls (overall p=0.0074). Single-cell RNA-sequencing of pooled aortic cells from lesioned aortas (n=3/group; 55,627 cells) identified SMCs as the most transcriptionally responsive cell type (172 differentially expressed genes), with enrichment of inflammatory pathways, including an interferon-g response, within two out of six distinct SMC subclusters in S961-treated mice. TRLs caused modest transcriptomic changes in cultured mouse aortic SMCs, but enrichment of the interferon-g response was observed after stimulation for 24 h with TRLs from S961-treated mice compared with SMCs stimulated with the same number of TRL particles from control mice (n=4, p=3.1x10^-5). In conclusion, these findings indicate that systemic IR promotes inflammatory activation of transcriptomically defined aortic SMC subpopulations in lesioned aortas and that these responses may be mediated in part by TRLs.