ABSTRACT
Title
Prolyl endopeptidase (Prep) regulates glucose sensing of VMN neurons, glucose metabolism and rebound feeding
Authors
G. D’Agostino1,2,3, Z-W. Liu1,2, R. Meli3, A. Calignano3,
S.n Wardlaw 4, T. L. Horvath1,2,5,6, X-B. Gao1,2 and S. Diano1,2,5,6
1Departments of Obstetrics, Gynecology & Reproductive Sciences, 2Program in Integrative Cell Signaling and Neurobiology of Metabolism, 5Section of Comparative Medicine, 6Neurobiology Yale University School of Medicine, New Haven, CT, USA. 4Department of Medecine, Columbia University, New York, USA. 3Department of Experimental Pharmacology, University of Naples “Federico II”, Naples, Italy.
1Departments of Obstetrics, Gynecology & Reproductive Sciences, 2Program in Integrative Cell Signaling and Neurobiology of Metabolism, 5Section of Comparative Medicine, 6Neurobiology Yale University School of Medicine, New Haven, CT, USA. 4Department of Medecine, Columbia University, New York, USA. 3Department of Experimental Pharmacology, University of Naples “Federico II”, Naples, Italy.
Abstract
Prolyl endopeptidase (Prep) has been implicated in regulation of neuronal functions, including hypothalamic processes. Here we report that Prep expression in the hypothalamus is predominantly present in the ventromedial nucleus (VMN). Knockout Prep(Prepgt/gt) mice had diminished POMC mRNA and peptides levels, increased rebound feeding and exhibited glucose intolerance compared to wild type controls. Concomitantly with these changes, Prepgt/gt mice showed reduced glucose-induced neuronal responses in the VMN, suppressed hypothalamic vesicular glutamate transporter 2 expression and decreased excitatory postsynaptic currents of POMC neurons. Altogether these data reveal a previously unsuspected mechanism of peptide processing in hypothalamic control of glucose metabolism and rebound feeding.