PYY(3-36) and exendin-4 reduce food intake and activate neuronal circuits in a synergistic manner in mice.

Peptide YY(3-36) ((PYY(3-36)) and glucagon like peptide 1 (GLP-1) in combination reduce food intake and body weight in an additive or synergistic manner in animal models and in humans. Nevertheless, the mechanisms behind are not completely understood. The present study aims to investigate the effect of combining PYY(3-36) and the GLP-1 receptor agonist exendin-4 (Ex4) by examining acute food intake and global neuronal activation as measured by c-fos in C57BL/6 J mice. An additive reduction in food intake was found 1.5 h after s.c dosing with the combination of PYY(3-36) (200 µg/kg) and Ex4 (2.5 µg/kg). This was associated with a synergistic enhancement of c-fos reactivity in central amygdalar nucleus (CeA), rostral part of the mediobasal arcuate nucleus (ARH), supratrigeminal nucleus (SUT), lateral parabrachial nucleus (PB), area postrema (AP) and nucleus tractus solitarius (NTS) compared to vehicle, PYY(3-36) and Ex4 individually dosed mice. The regions activated by Ex4 individually and PYY(3-36) and Ex4 in combination resembled each other, but the combination group had a significantly stronger c-fos response. Twenty-five brain areas were activated by PYY(3-36) and Ex4 in combination compared to vehicle versus nine brain areas by Ex4 individually. No significant increase in c-fos reactivity was found by PYY(3-36) compared to vehicle dosed mice. The neuronal activation of ARH and the AP/NTS to PB to CeA pathway is important for appetite regulation while SUT has not previously been reported in the regulation of energy balance. As PYY(3-36) and Ex4 act on different neurons leading to recruitment of different signalling pathways within and to the brain, an interaction of these pathways may contribute to their additive/synergistic action. Thus, PYY(3-36) boosts the effect of Ex4 possibly by inducing less inhibition of neuronal activity leading to an enhanced neuronal activity induced by Ex4.

Integrated Brain Atlas for Unbiased Mapping of Nervous System Effects Following Liraglutide Treatment.

Light Sheet Fluorescence Microscopy (LSFM) of whole organs, in particular the brain, offers a plethora of biological data imaged in 3D. This technique is however often hindered by cumbersome non-automated analysis methods. Here we describe an approach to fully automate the analysis by integrating with data from the Allen Institute of Brain Science (AIBS), to provide precise assessment of the distribution and action of peptide-based pharmaceuticals in the brain. To illustrate this approach, we examined the acute central nervous system effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Peripherally administered liraglutide accessed the hypothalamus and brainstem, and led to activation in several brain regions of which most were intersected by projections from neurons in the lateral parabrachial nucleus. Collectively, we provide a rapid and unbiased analytical framework for LSFM data which enables quantification and exploration based on data from AIBS to support basic and translational discovery.