Deletion of leptin signaling in vagal afferent neurons results in hyperphagia and obesity

The vagal afferent pathway senses hormones released from the gut in response to nutritional cues and relays these signals to the brain. We tested the hypothesis that leptin resistance in vagal afferent neurons (VAN) is responsible for the onset of hyperphagia by developing a novel conditional knockout mouse to delete leptin receptor selectively in sensory neurons (Nav1.8/LepR(fl/fl) mice). Chow fed Nav1.8/LepR(fl/fl) mice weighed significantly more and had increased adiposity compared with wildtype mice. Cumulative food intake, meal size, and meal duration in the dark phase were increased in Nav1.8/LepR(fl/fl) mice; energy expenditure was unaltered. Reduced satiation in Nav1.8/LepR(fl/fl) mice is in part due to reduced sensitivity of VAN to CCK and the subsequent loss of VAN plasticity. Crucially Nav1.8/LepR(fl/fl) mice did not gain further weight in response to a high fat diet. We conclude that disruption of leptin signaling in VAN is sufficient and necessary to promote hyperphagia and obesity. (C) 2014 The Authors. Published by Elsevier GmbH.