Leptin, a peptide hormone produced by white adipose tissue in proportion to energy stores, plays a central role in the control of feeding and energy balance. Leptin receptor (LepRb) mainly signals trough activation of signal transducer and activator of transcription 3 (STAT3); however, there is also a second, yet unidentified signal. Barnes et al. used CRISPR/Cas9-mediated mutagenesis to generate a panel of mouse lines containing truncations of LepRb. By studying these five novel mouse lines, they identified a region of the intracellular LepRb that is required to mediate the second signal and additionally found a region that mediates a previously undescribed LepRb inhibitory signal.