An obesity-associated switch in vagal gut-brain communication modulates feeding behavior

In obesity, disruption of gut-brain communication has been associated with overeating, body weight gain, and metabolism disorders. Vagal sensory neurons (VSN) relay nutrient-related signals from the gut to the brain, but how distinct, gut-innervating VSN subtypes are affected by obesity remains unclear. We employed an intersectional genetic approach to investigate obesity-induced functional changes in molecularly defined VSN subtypes that innervate the stomach and small intestine. We demonstrate that overexpression of the suppressor of cytokine signaling 3 (Socs3), a crucial regulator of leptin signaling, in small-intestine-innervating VSN dramatically alters feeding behavior. By contrast, Socs3 overexpression in stomach-innervating VSN has no effect. Furthermore, selective chemogenetic manipulations after exposure to a high fat diet (HFD) show that intestine-innervating VSN become sufficient to drive feeding behavior. Our results demonstrate that obesity-associated increases in Socs3 levels selectively trigger a functional switch in intestine-innervating VSN which may contribute to obesity-associated disruption of gut-brain communication.