Using electron microscopy, researchers have amassed new insights about how the hormone leptin interacts with its receptor (Mol. Cell, DOI: 10.1016/j.molcel.2012.09.003). Signals from leptin, which is secreted by fat tissue, affect metabolism. This biochemical pathway has intrigued obesity drug researchers for more than a decade. But the arrangement of leptin’s signaling complex is in dispute, with camps proposing either a 2:2 or a 2:4 ratio of leptin to its receptor. Georgios Skiniotis and colleagues at the University of Michigan now provide strong evidence that the ratio is 2:2. They observed two copies of leptin that engaged two copies of the rod-shaped receptor, locking the floppy rods into place. They propose that this locking mechanism is key for signaling. The next step, Skiniotis says, will be to determine a structure of the complex that includes Janus kinase, an enzyme that mediates leptin signaling and is itself a drug target for cancer and immune disorders. Skiniotis adds that the mechanism of leptin signaling parallels that of related proteins, such as interleukin-6, which is implicated in cancer.