Manganese-enhanced MRI demonstrates that oxyntomodulin and GLP-1 affect neuronal activity in distinct regions of the brain
Owais Chaudhri1, James Parkinson1, Amy Herlihy2, Victoria Salem1, Yu-Ting Kuo4, Jimmy Bell3, Po-Wah So2, Waljit Dhillo1, Sarah Stanley1, Mohammad Ghatei1 & Steve Bloom1
The rise in the prevalence of obesity has imparted urgency to the study of the mechanisms of appetite regulation. Oxyntomodulin (OXM) and glucagon-like peptide-1 (GLP-1) are anorexigenic gut hormones thought to act via the same receptor. There is an increasing body of evidence, however, that they may act via distinct pathways. Magnetic resonance imaging (MRI) is increasingly being used as a tool for tracking changes in neuronal activity in vivo through time. Manganese-enhanced MRI (MEMRI) uses Mn2+ ions as an activity-dependent contrast agent.
Aims: Here we use MEMRI to compare the patterns of neuronal activity in key appetite-modulating regions of the mouse CNS following systemic OXM and GLP-1 administration.
Methods: C57Bl/6 mice were anaesthetised with isoflurane and scanned in a 9.4T scanner. Images were obtained following intravenous infusion of Mn2+ and intraperitoneal injection of peptide or vehicle. Four experimental groups were studied: vehicle-injected mice allowed ad libitum access to chow; vehicle-injected mice fasted for 16 hours prior to scanning; and 16-hour fasted mice injected with OXM (1400 nmol/kg) or GLP-1 (900 nmol/kg). Regions of interest (ROI) were defined for image analysis based on areas known to be involved in the regulation of feeding: arcuate nucleus (ARC), paraventricular nucleus (PVN), supraoptic nucleus (SON), ventromedial hypothalamus (VMH) and area postrema (AP).
Results: Significant differences in signal intensity (SI) were seen between fasted and non-fasted mice in the ARC, PVN, SON and AP. OXM administered to fasted mice resulted in SI profiles in the ARC, SON and AP that were not significantly different to those of non-fasted mice. GLP-1, however, caused significant changes in SI in the PVN, VMH and AP.
Conclusions: These novel findings are consistent with the role of these peptides as endogenous satiety factors and confirm that OXM and GLP-1 may be acting via distinct pathways with the CNS