Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l+/− mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration. In the hypothalamus of Rpgrip1l+/− mice, and in human fibroblasts with hypomorphic mutations in RPGRIP1L, the number of AcIII-positive cilia is diminished, accompanied by impaired convening of the leptin receptor to the vicinity of the cilium, and diminished pStat3 in response to leptin. These findings suggest that RPGRIP1L may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus. Display omitted •Mice heterozygous for a null Rpgrip1l allele are fatter than wild-type controls•Leptin signaling is diminished in the hypothalami of Rpgrip1l+/− mice•The localization of the leptin receptor is perturbed in Rpgrip1l+/− mice•RPGRIP1L may account for part or all of the association of the FTO locus with BMI Common polymorphisms in the first intron of the Fat Mass and Obesity-Associated (FTO) gene are linked with increased body weight in adults. Stratigopoulos et al. show that the nearby ciliary gene, RPGRIP1L, could be responsible for the obesity susceptibility signal at the FTO locus.