Direct interoceptive input to the insular cortex shapes learned feeding behavior

The insular cortex (insula) is an interoceptive hub, which senses internal states such as hunger, thirst, pain, and emotions. Previous studies suggest that the insula directly senses internal states, but the mechanisms remain elusive. We identified a population of leptin receptor-positive cells with a unique morphology in the insula (INS^LepR). Based on leptin's known role in signaling adiposity, we hypothesized that INS^LepR neurons detect internal states to regulate food intake and body weight. Accordingly, we found that intra-insula leptin administration or optogenetic stimulation of INS^LepR neurons impacts feeding behavior. Moreover, INS^LepR neuron activity encodes feeding bouts in an internal-state dependent manner, and leptin alters insula neural dynamics in response to feeding, while also reshaping the transcriptome. Taken together, our data supports a model for direct interoceptive input to the insula, in which INS^LepR cells integrate adiposity level signals to regulate feeding and body weight in a learned manner.