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Introduction: Through exosome-mediated transportation, long noncoding RNAs (lncRNAs) can influence cellular function and mediate cross-talk among organ systems. However, current understanding of the roles of exosomal lncRNAs in the context of insulin resistance (IR) remains limited. Accordingly, this study was developed to examine patterns of differential lncRNA expression in blood-derived exosomes from a murine high-fat diet-associated IR (HFD-IR) mice model and to explore the functions of these lncRNAs. Methods: A microarray approach was used to assess the differential patterns of lncRNA expression in blood-derived exosomes when comparing control and HFD-IR mice. The observed changes in lncRNA expression were also validated in blood and skeletal muscle from obesity-associated IR model mice and in C2C12 myotubes that had been subjected to high-dose 0.5 mM palmitate treatment. Further studies of the origins of exosomal lncRNA AK018453 were performed through the use of siRNAs and exosomes that had been labeled with PKH26. Results: In total, HFD-IR mice exhibited 375 lncRNAs that were differentially expressed in their blood-derived exosomes as compared to healthy control mice. Pathway and gene set enrichment analyses suggested these targets to be enriched in the NF-kB, PI3K-Akt, Wnt, JAK/STAT, and glucagon signaling pathways. Additional studies revealed that these exosome-derived lncRNAs contained binding sites for several miRNAs, some of which were related to the IR process. Functional studies suggested that the adipose-derived exosomal lncRNA AK018453 was associated with IR and could be taken up by skeletal muscle tissue. Conclusion: The results of these analyses indicated that obesity-associated IR results in the dysregulation of exosomal lncRNA expression in mice, while also supporting the ability of the lncRNAs within these exosomes to mediate cross-talk between adipose and skeletal muscle tissue, thereby potentially shaping the pathogenesis of obesity-associated IR.