APPL1 (adaptor protein containing PH domain, PTB domain and leucine zipper motif-1) has been established as an important mediator of insulin and adiponectin signaling. Here we investigated the influence of transgenic (Tg) APPL1 overexpression in mice on high fat diet (HFD) induced cardiomyopathy in mice. Wild type (Wt) mice fed a high fat diet for 16 weeks showed cardiac dysfunction, determined by echocardiography, with decreased ejection fraction, decreased fractional shortening and increased end diastolic volume. HFD-fed APPL1 Tg mice were significantly protected from this dysfunction. Speckle tracking echocardiography to accurately assess cardiac tissue deformation strain and wall motion also indicated dysfunction in Wt mice and a similar improvement in Tg versus Wt mice on HFD. APPL1 Tg mice had less HFD-induced increase in circulating non-esteridied fatty acid levels and myocardial lipid accumulation. Lipidomic analysis using LC-MS/MS showed HFD significantly increased myocardial contents of distinct ceramide, sphingomyelin and diacylglycerol (DAG) species, of which increases in C16:0 and C18:0 ceramides plus C16:0 and C18:1 DAGs were attenuated in Tg mice. Glucose tolerance test indicated less peripheral insulin resistance in response to HFD in Tg mice which was also apparent by measuring cardiac Akt phosphorylation and cardiomyocyte glucose uptake. In summary, APPL1 Tg mice exhibit improved peripheral metabolism, reduced cardiac lipotoxicity and improved insulin sensitivity. These cellular effects contribute to protection from HFD-induced cardiomyopathy.