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

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.