Distinct Regulation of Orexigenic and Anorexigenic Hypothalamic Pathways in Creatine-Deficient Mice

A. Neu; M. Stockebrand; D. Isbrandt; C. U. Choe

doi:10.1055/s-0037-1602976

Neuropediatrics, Table of Contents

Neuropediatrics 2017; 48(S 01): S1-S45
DOI: 10.1055/s-0037-1602976

P – Poster

Georg Thieme Verlag KG Stuttgart · New York

Distinct Regulation of Orexigenic and Anorexigenic Hypothalamic Pathways in Creatine-Deficient Mice

Authors

A. Neu

¹Department of Pediatrics and 3 Neurology, UKE, Hamburg, Germany
M. Stockebrand

²Experimental Neurophysiology, DZNE, Bonn and University of Cologne, Cologne, Germany
D. Isbrandt

²Experimental Neurophysiology, DZNE, Bonn and University of Cologne, Cologne, Germany
C. U. Choe

³Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Abstract

Full Text

Background/Purpose: The central role of creatine (Cr) in brain is emphasized by neurometabolic disorders caused by Cr deficiency. Cr synthesis takes place by L-arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) mainly in kidney and liver. In AGAT−/− mice, Cr deficiency protects from diet-induced obesity and metabolic syndrome. Biochemical analyses revealed chronic, Cr-dependent AMPK activation in brain, skeletal muscle, adipose tissue and liver of AGAT−/− mice. Partial leptin dependence of this phenotype indicated a contribution of the central nervous system (CNS), where the adipocyte-derived hormone leptin exerts its main effects. We therefore analyzed how CNS-mediated regulation of whole-body metabolism is influenced by Cr.

Methods: Feeding behavior of AGAT−/− mice was analyzed following injection of ghrelin or leptin. Activity of NPY- and POMC-positive neurons was determined by immunohistochemistry and direct electrophysiological recordings.

Results: In Cr-deficient AGAT−/− mice, we found reduced effects of the orexigenic hormone ghrelin on feeding behavior. In addition, we detected augmented electrical activity of arcuate NPY neurons under baseline conditions in AGAT−/− mice. Markers of cellular activation (c-Fos) were elevated in arcuate NPY- but not POMC-neurons in mediobasal hypothalamus

Conclusion: Disease models of Cr deficiency syndromes can be used to disentangle the role of Cr in neuronal subpopulations. Our findings suggest major contributions of Cr in CNS regulation of whole-body metabolism via NPY-expressing hypothalamic neurons.