Mammalian leptin (LEP) is a pleiotropic peptide hormone best characterized for its roles related to obesity and diabetes. However, the molecular function of the leptin signal transduction pathway in non-mammals is less clear. Comparative studies that address leptin signaling in non-model organisms are integral components of the leptin phylogenetic history, and there is little evidence addressing the functional disparities between the teleost leptin paralogues and mammalian leptins. To demarcate genes and biochemical pathways regulated by leptin signaling in developing zebrafish, microarray gene expression data were generated with total RNA isolated at 48 hours post fertilization from leptin-a morpholino oligonucleotide “knockdown”, recombinant leptin-a “rescue”, and wild type embryos. Expression estimates were computed for 26,046 genes across 16 microarray samples. Differentially expressed genes (DEG), (KEGG) pathways, and Gene Ontologies (GO) were evaluated for three contrasts (Morphant:Control, Rescue:Morphant, Rescue:Control). Signaling pathways that respond to leptin-a knockdown and rescue are analogous to gene targets of the mammalian LEP system (“GnRH”, “MAPK”, “Adipocytokine”, “Phosphatidylinositol”, “mTOR”, “ErbB”, “FoxO”, and “Notch”). A subset of differentially expressed transcription factors in leptin-a morphants are homologous to putative regulators of LEP expression in mammals (cebpb, creb5, fosl1a, mybl1, pax5, pou3f1, pparg, stat1a). “Neuroactive ligand-receptor interaction” as well as cAMP-responsive hormone signaling pathways responded to leptin-a. Consistent with leptin-a as an endocrine regulator, agouti-related peptide-2 (agrp2), cocaine-and-amphetamine-related-transcript (LOC557301), gonadotropin-releasing hormone 2 (gnrh2), and melanocortin receptor 5a (mc5ra) were dysregulated in rescue embryos. Further, “Notch signaling” and “Spinal cord/CNS development” were enriched in morphants whereas rescue arrays were comparable to wild type expression. Together with upregulated odorant receptors and “G-protein signaling” in rescue embryos, these data signify that embryonic leptin-a serves a pleiotropic role in zebrafish sensory system development and neurogenesis, endocrine physiology, and lipid signaling. “p53 signaling”, “Ribosome biogenesis”, and “mRNA surveillance pathway” were over-represented in leptin-a morphants including components of the RNA-induced-silencing-complex (protein argonaute-1-like (LOC570775)) which is consistent with activation of RNA interference pathways. Collations between the leptin-a knockdown dataset and un-related morpholino expression data suggest that “p53 signaling” and “Phototransduction” are ubiquitous responses to morpholino knockdown. However, additional molecular and biochemical analyses are needed to validate these assertions.