PYY3-36 and pancreatic polypeptide reduce food intake in an additive manner via distinct hypothalamic dependent pathways in mice

Objective: PYY3-36 and PP potently inhibit food intake in rodents and humans, however, it is unclear whether they have any synergistic/additive interaction in decreasing food intake. Design and Methods: Fasted WT, Y2-/- , Y4-/- or Y2Y4-/- mice were i.p. administrated with saline, PYY3-36 and/or PP. Results: We demonstrate that combined injection of PYY3-36 and PP reduces food intake in an additive manner. This effect is mediated via Y2 and Y4 receptors, respectively. We demonstrate that PYY3-36 and PP activate distinct neuronal pathways in the hypothalamus, as demonstrated by immunostaining for c-fos, which shows distinct patterns in response to either hormone. After PYY3-36 injection, neurons in the dorsal aspect of the Arc, PVN and DMH are activated with minimal responses seen in the VMH and LHA of WT mice. These effects are absent in Y2-/- mice. PP activates preferably the lateral aspect of the Arc, the DMH, VMH and LHA in a Y4 receptor-dependent manner. Importantly, the expression pattern of c-fos immunoreactive neurons induced by combined treatment appears to be the sum of the effects of single treatments rather than a result of synergistic interaction. Conclusions: These findings demonstrate that PYY3-36 and PP activate distinct pathways in the hypothalamus to reduce food intake in an additive manner.