Peptide YY3-36 and pancreatic polypeptide differentially regulate hypothalamic neuronal activity in mice in vivo as measured by manganese-enhanced magnetic resonance imaging

Peptide YY (PYY) and pancreatic polypeptide (PP) are two appetite suppressing hormones, released post-prandially from the ileum and pancreas, respectively. PYY3-36, the major circulating form of the peptide, is considered to reduce food intake in humans and rodents via high affinity binding to the auto-inhibitory neuropeptide Y receptor Y2R, whereas PP is considered to act through the Y4R. Current evidence indicates the anorexigenic effects of both peptides occur via signalling in the brainstem and arcuate nucleus (ARC) of the hypothalamus. Manganese-enhanced magnetic resonance imaging (MEMRI) has previously been used to track hypothalamic neuronal activity in vivo in response to both nutritional interventions and gut hormone treatment. In the present study, we used MEMRI to demonstrate that s.c. administration of PP results in a significant reduction in signal intensity (SI) in the ARC, ventromedial hypothalamus and paraventricular nucleus of fasted mice. Subcutaneous delivery of PYY3-36 resulted in a nonsignificant trend towards decreased SI in the hypothalamus of fasted mice. We found no SI change in the area postrema of the brainstem after s.c. injection of either peptide. These differences in hypothalamic SI profile between PP and PYY3-36 occurred despite both peptides producing a comparable reduction in food intake. These results suggest that separate central pathways control the anorexigenic response for PP and PYY3-36, possibly via a differential effect of Y4 receptor versus Y2 receptor signalling. In addition, we performed a series of MEMRI scans at 0–2, 2–4 and 4–6 h post-injection of PYY3-36 and a potent analogue of the peptide; PYY3-36 (LT). We recorded a significant reduction in the ARC SI 2–4 h after PYY3-36 (LT) injection compared to both saline and PYY3-36 in fasted mice. The physiological differences between PYY3-36 and its analogue were also observed in the long-term effects on food intake, with PYY3-36 (LT) producing a more sustained anorexigenic effect. These data suggest that MEMRI can be used to investigate the long-term effects of gut peptide delivery on activity within the hypothalamus and brainstem