Intraportal administration of DPP-IV inhibitor regulates insulin secretion and food intake mediated by the hepatic vagal afferent nerve in rats

J. Neurochem. (2012) 121, 66–76. Glucagon‐like peptide‐1 (GLP‐1) stimulates insulin secretion and suppresses food intake. Recent studies indicate that the hepatic vagal afferent nerve is involved in this response. Dipeptidyl peptidase‐IV (DPP‐IV) inhibitor extends the half‐life of endogenous GLP‐1 by preventing its degradation. This study aimed to determine whether DPP‐IV inhibitor‐induced elevation of portal GLP‐1 levels affect insulin secretion and feeding behavior via the vagal afferent nerve and hypothalamus. The effect of DPP‐IV inhibitor infusion into the portal vein or peritoneum on portal and peripheral GLP‐1 levels, food intake, and plasma insulin and glucose was examined in sham‐operated and vagotomized male Sprague–Dawley rats. Analyses of neuronal histamine turnover and immunohistochemistry were used to identify the CNS pathway that mediated the response. Intraportal administration of the DPP‐IV inhibitor significantly increased portal (but not peripheral) GLP‐1 levels, increased insulin levels, and decreased glucose levels. The DPP‐IV inhibitor suppressed 1‐ and 12‐ but not 24‐h cumulative food intake. Intraportal infusion of the DPP‐IV inhibitor increased hypothalamic neuronal histamine turnover and increased c‐fos expression in several areas of the brain. These responses were blocked by vagotomy. Our results indicate that DPP‐IV inhibitor‐induced changes in portal but not systemic GLP‐1 levels affect insulin secretion and food intake. Furthermore, our findings suggest that a neuronal pathway that includes the hepatic vagal afferent nerve and hypothalamic neuronal histamine plays an important role in the pharmacological actions of DPP‐IV inhibitor. Neuronal pathways for glucose metabolism and feeding behavior Glucagon‐like peptide‐1 (GLP‐1), rapidly degraded by dipeptidyl peptidase‐IV (DPP‐IV), affects glucose metabolism and feeding behavior. DPP‐IV inhibitor‐induced changes in portal but not systemic GLP‐1 levels stimulate insulin secretion and suppress feeding, which are blocked by vagotomy, indicating a neuronal pathway that includes the hepatic vagal afferent nerve plays an important role in the pharmacological actions of DPP‐IV inhibitor.