RPGRIP1L is one of several genes located in the obesity-associated FTO region, and the risk-associated SNP in intron 1 of FTO has been proposed to influence RPGRIP1L expression. To further evaluate a potential role for RPGRIP1L in obesity-related traits, George Stratigopoulos, Rudolph Leibel and colleagues (Cell Metab. 19, 767–779, 2014) examined the phenotype of mice heterozygous for a null allele of Rpgrip1l. They found that these mice exhibited increased weight gain and markedly increased adiposity, accompanied by increased energy intake and increased serum leptin levels. Because RPGRIP1L has previously been implicated in regulating trafficking of the leptin receptor (Lepr) to cilia, the authors examined the hypothalamus in Rpgrip1l heterozygous mice and observed reduced levels of Lepr ciliary localization and of downstream markers of leptin signaling. They also observed increased expression of orexigenic genes encoding Neuropeptide Y (Npy) and Agouti-related protein (Agrp) in the hypothalamus of Rpgrip1l heterozygous mice compared to wild-type controls. These findings support the hypothesis that the effects of the obesity-associated SNP in the FTO region might be mediated, in part, through altered RPGRIP1L expression and downstream effects on leptin signaling.