Joe gave an erudite, subtle and detailed description of his team’s exploration of novel mechanisms involved in the pathogenesis of obesity. This work was recently published in Science. Joe described in depth the involvement of the MRAP-2 gene and its role in both fat metabolism and food seeking behavior and consumption. He tied his work in identifying mutations in this gene in humans that result in obesity to knock out mouse studies that reiterate these features. Joe also delved into the details of how MRAP2 interfaces with GPCR, Mc4R including a discussion of how GPCRs could potentially continue signaling following internalization. One of the most exciting and striking findings described was that Mrap-2 knockout mice gained weight faster than mice with the functional gene despite being given the exact same diet as the control mice. Mrap-2 K.O. mice also had identical activity levels as controls and absorbed the same amount of “food value” from their equi-caloric diet. In other words, their energy usage appeared more efficient than controls and even occurred when they were systematically underfed. This raised much discussion about the mechanism for this effect. The take away message from all of Joe’s work was that elegant discovery and translational work can be done hand in hand and that the human condition can inform in vivo murine experiments and vice versa. Joe subsequently showed how he had identified patients with mutations in the mrap2 gene that were associated with an obese phenotype. This clearly opens the field for exploration of new mutations in this receptor/ligand axis or closely associated upstream signaling pathways that contribute to obesity.