Modified peptide YY molecule attenuates the activity of NPY/AgRP neurons and reduces food intake in male mice

OBJECTIVES: To study the effects of an analogue of the gut-produced hormone peptide YY (PYY3-36), which has increased selectivity for the Y2 receptor; specifically, to record its effects on food intake and on hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron activity. METHODS: NNC0165-1273, a modified form of the peptide hormone PYY3-36 with potent selectivity at Y2 receptor (>5000 fold over Y1, 1250 fold over Y4 and 650 fold over Y5 receptor), was tested in vivo and in vitro in mouse models.NNC0165-1273 has 5-fold lower relative affinity for Y2 compared to PYY3-36, but >250, 192 and 400-fold higher selectivity, respectively, for the Y1, Y4 and Y5 receptors. RESULTS: NNC0165-1273 produced a reduction in night-time feeding at a dose at which PYY3-36 loses efficacy. The normal behavioural satiety sequence observed suggests that NNC0165-1273 is not nauseating and, instead, reduces food intake by producing early satiety. Additionally, NNC0165-1273 blocked ghrelin-induced cFos expression in NPY/AgRP neurons. In vitro electrophysiological recordings showed that, opposite to ghrelin, NNC0165-1273 hyperpolarised NPY/AgRP neurons and reduced action potential frequency. Administration of NNC0165-1273 via subcutaneous osmotic minipump caused a dose-dependent decrease in body weight and fat mass in an obese mouse model. Finally, NNC0165-1273 attenuated the feeding response when NPY/AgRP neurons were activated using ghrelin or more selectively with designer receptors. CONCLUSIONS: NNC0165-1273 is non-nauseating and stimulates a satiety response through, at least in part, a direct action on hypothalamic NPY/AgRP neurons. Modification of PYY3-36 to produce compounds with increased affinity to Y2 receptors may be useful as anti-obesity therapies in humans.