An H2R-dependent medial septum histaminergic circuit mediates feeding behavior

Novel targets for treating feeding-related diseases are of great importance, and histamine has long been considered an anorexigenic agent. However, understanding its functions in feeding in a circuit-specific way is still limited. Here, we report a medial septum (MS)-projecting histaminergic circuit mediating feeding behavior. This MS-projecting histaminergic circuit is functionally inhibited during food consumption, and bidirectionally modulates feeding behavior via downstream H2, but not H1, receptors on MS glutamatergic neurons. Further, we observed a pathological decrease of histamine 2 receptors (H2Rs) expression in MS glutamatergic neurons in diet-induced obesity (DIO) mice. Genetically, down-regulation of H2Rs expression in MS glutamatergic neurons accelerates body-weight gain. Importantly, chronic activation of H2Rs in MS glutamatergic neurons (with its clinical agonist amthamine) significantly slowed down the body-weight gain in DIO mice, providing a possible clinical utility to treat obesity. Together, our results demonstrate that this MS-projecting histaminergic circuit is critically involved in feeding, and H2Rs in MS glutamatergic neurons is a promising target for treating body-weight problems.