Project Summary/Abstract Obesity remains one of the largest unmet medical needs facing the US healthcare system. More than one in three adults in the US are obese and these rates continue to increase with the most severe category of obesity unfortunately growing the fastest. It is hard to overstate the human and monetary costs to the individuals impacted and society as a whole. It remains that very few of these individuals receive effective therapies. The existing behavioral interventions have limited efficacy. While the approved pharmacological therapies are more successful, none of the currently approved therapies produce even 10% sustained body weight loss on a placebo-adjusted basis. Consequently, there is still an enormous need for additional pharmacological treatments for individuals with obesity. Growth differentiation factor 15 is a member of the TGFβ superfamily that has been linked to the anorexia and weight loss that occurs with some cancers. This launched a number of programs to harness GDF15 analogues as obesity therapeutics and to identify the receptor that mediates these effects. Such efforts culminated in a series of 4 high-profile papers published in late 2017 that each identified GDNF family receptor α-like (GFRAL) as a high affinity receptor for GDF15 and is absolutely required for the potent effects of GDF15 to reduce food intake and body weight. Interestingly, GFRAL is almost exclusively expressed in the CNS. Moreover, its distribution in the CNS is almost entirely limited to a brainstem area termed the area postrema which sits outside the blood-brain barrier. Given the powerful weight loss effects of GDF15 mediated by this small population of neurons, it points to a very important role of these neurons to regulate food intake and energy balance. We have built state-of-the-art mouse models that will allow us to selectively identify, track and manipulate these neurons. To that end, we will identify the projections from these neurons both within the caudal portion of the brainstem and to hypothalamic areas that have been linked to the regulation of body weight. We will also use these tools to selectively activate or silence these neurons and assess their role in normal control of energy balance and to mediate the effects of other weight loss manipulations. This work has enormous significance and novelty. GDF15 is one of the most promising new treatment strategies for obese individuals. Maybe even more importantly, the potent effects of GDF15 point to a novel CNS circuit engaged from a very small population of neurons located in the area postrema. Establishing components of this circuit and key aspects of GDF15 biology will maximize the potential utility of GDF15 as a therapeutic and identify new targets that target key components of this system.