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

• Published in: Neuropeptides (Edinburgh) Vol. 73; pp. 89 - 95
• Main Authors: Kjaergaard, Marina, Salinas, Casper Bo Gravesen, Rehfeld, Jens F., Secher, Anna, Raun, Kirsten, Wulff, Birgitte S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.02.2019; Elsevier Science Ltd
• Subjects: Amygdala - drug effects; Amygdala - metabolism; Animal models; Animals; Appetite; Arcuate nucleus; Area postrema; Body weight; Body Weight - drug effects; c-Fos protein; Dosage; Eating - drug effects; Energy balance; Exenatide - pharmacology; Exendin-4; Food; Food additives; Food intake; Global c-fos; Glucagon; Hypothalamus - drug effects; Hypothalamus - metabolism; Mice; Neurons - drug effects; Neurons - metabolism; Parabrachial nucleus; Peptide Fragments - pharmacology; Peptide YY - pharmacology; Peptides; Proto-Oncogene Proteins c-fos - metabolism; PYY(3-36); Rodents; Signal transduction; Solitary tract nucleus; Synergy; TU; DG; PVH; LS; DR; PVT; PYY(3-36); Exendin-4; MPT; CA1; CA3; CA2; GENd; ME; PSTN; IC; AgRP; MH; SCm; V4; MM; BST; Global c-fos; PVp; AP; ZI; MEPO; SUT; PCG; BLA; VL; ARH; SEM; NI; CART; GLP-1R; Ex4; VTA; LHA; LRNm; MRN; AUDd; LPO; NTS; NLL; SF; AOB; COA; NPY; BMA; Synergy; RHP; SFO; DMH; ACB; Appetite; GLP-1; TTd; OV; SNc; DMX; POMC; VMH; CU; PB; ECU; SNr; ECT; LC; PAG; PG; PH; Veh; SCH; Y2; LH; CeA
• ISSN: 0143-4179; 1532-2785
• DOI: 10.1016/j.npep.2018.11.004

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. •c-fos analyzed by iDISCO immunostaining and 3D imaging gave the unique possibility to study global brain c-fos reactivity.•Ex4 alone induced significant c-fos immunoreactivity in 9 brain regions and no effect by PYY(3-36) compared to vehicle.•PYY(3-36) and Ex4 in combination induced significant c-fos immunoreactivity in 25 brain regions compared to vehicle.•Within the mediobasal ARH and AP/NTS/PB/CeA anorectic pathway a synergistic c-fos response was found by PYY(3-36) and Ex4.•PYY(3-36) and Ex4 also activated LRNm and SUT which not previously has been reported in the regulation of energy homeostasis.