Hereditary components are responsible for 40-70% of variation in body weight and obesity, yet we currently know only ~5% of the underlying causal genes. In order to develop new treatments for obesity, we must develop a mechanistic understanding of the pathways in which the other 95% of predisposing alleles normally function. We previously developed a novel, buoyancy-based assay for body fat in Drosophila larvae and used it in an unbiased forward genetic screen to identify split ends (spen) as a new fat regulator. Spen is an RNA-binding protein previously implicated in transcriptional control of conserved signaling pathways. Interestingly, despite being fat, larvae in which Spen is depleted from the fat body (FB) are sensitive to starvation, suggesting that these animals are incapable of using their excess fat stores. Consistent with this phenotype, metabolomics and RNAseq demonstrate metabolic alterations in Spen-depleted FBs indicative of a defect in mobilization of energy stores, and utilization of other metabolites (proteins and carbohydrates) as primary sources of energy. We further find that Spen function is necessary and sufficient to promote fat depletion in the FB, and that another Spen family member, Spenito (Nito), plays an opposing role in fat storage. FB overexpression of an N-terminal Spen fragment containing the RNA Recognition Motifs (RRMs) causes a dominant-negative high-fat phenotype, whereas overexpression of a C-terminal fragment lacking the RRMs but containing a nuclear localization signal and the conserved Spen paralog and ortholog (SPOC) domain had no effect on larval buoyancy. Thus, the RRMs are required for the ability of overexpressed full-length Spen to deplete fat stores, and when overexpressed alone may sequester important Spen-associated RNAs into non-functional complexes. We propose that Nito, which contains RRMs and a SPOC domain but is much smaller than Spen, may act as a negative regulator of Spen function. Finally, we find that the mammalian Spen ortholog also regulates fat storage in cultured adipocytes. No other study has implicated Spen in the regulation of metabolism or body fat control. Our work provides a new direction for understanding metabolic disease as well as a molecular handle to generate novel mechanistic insights into the causes of obesity.