Lipid dysregulation is a key contributor to the pathogenesis of obesity and its related disorders. The heart has emerged as an important organ in the regulation of systemic lipid homeostasis; however, the underlying mechanism remains poorly understood. Here, we show that Drosophila cardiomyocytes control systemic lipid metabolism by expressing mtp and apoLpp, genes so far known to be essential for apoB-lipoprotein biosynthesis only in the fat body (insect adipose tissue and liver). We found that on normal food diet, knockdown of mtp or apoLpp in the fat body or cardiomyocytes decreases systemic triglyceride (TG) levels, suggesting equal contribution of the cardiomyocyte- and fat body-derived apoB-lipoproteins in the regulation of whole-body lipid metabolism. Unexpectedly, on high fat diet (HFD), knockdown of mtp or apoLpp in the cardiomyocytes, but not in fat body, protects against the gain in systemic TG levels, suggesting that cardiomyocyte-derived apoB-lipoproteins are the predominant regulators of systemic lipid metabolism in response to HFD. We further found that HFD significantly up-regulates mtp and apoLpp expression in the cardiomyocytes, but paradoxically down-regulate their expression in the fat body, culminating in higher Mtp and apoLpp levels in the cardiomyocytes than in fat body and possibly underlying the differential systemic metabolic effects of apoB-lipoprotein inhibition in the cardiomyocytes versus the fat body. Our findings reveal a novel and significant function of heart-mediated apoB-lipoproteins in the control of systemic lipid homeostasis.