Y2 receptor agonism and AgRP neurons in the co-ordinated control of energy balance

Abstract

AgRP/NPY neurons are a discrete population with expression limited to the hypothalamic arcuate nucleus. They are orexigenic, forming a critical component of the appetite-regulating melanocortin system. AgRP/NPY neurons respond to energy-relevant hormones and neuronal input. They are regulated by the inhibitory Y2 ‘autoreceptor’, which is activated by the ‘satiety hormone’ PYY3-36, a major facilitator of the satiety response. Due to this inhibitory effect on feeding, PYY3-36 and Y2 receptors are potentially valuable therapeutic targets for the treatment of obesity. PYY3-36 analogues have been developed, including NN-1273, which possesses 5,000 times selectivity at the Y2 receptor compared to the orexigenic Y1 receptor, 750 times selectivity compared to orexigenic Y5 receptors, as well as an increased circulating half-life over PYY3-36. We performed several behavioural experiments to determine the effects of NN-1273. NN-1273 blocked ghrelin induced feeding and caused a dose-dependent reduction in normal night-time feeding. Through measurement of the behavioural satiety sequence (BSS), NN-1273 reduced food intake through induction of physiological satiety and was therefore, not nauseating at the experimental dose. C-Fos analysis revealed that NN-1273 attenuated ghrelin – induced c-Fos expression in AgRP/NPY neurons and electrophysiological recordings showed that NN-1273 reduced AgRP/NPY neuron action potential frequency. Optogenetic interrogation of AgRP/NPY neurons and major projection sites in the PVT and LHA support AgRP/NPY neurons as prime drivers of feeding behaviour and show that downstream projection pathways to the LHA play an important role in blood-glucose regulation via the modulation of peripheral insulin resistance. AgRP/NPY neurons possess myriad downstream projections that contribute to global energy metabolism including feeding and blood-glucose regulation. The function of their projections, especially to the PVT, remain poorly understood in the context of energy homeostasis and worthy of continued investigation. Although gastric bypass surgery remains the gold-standard for the treatment of obesity, effective pharmaceutical interventions would alleviate the need for serious surgery whilst still facilitating a reduction in body weight. NN-1273 is a non-nauseating and potent suppressor of feeding behaviour which functions largely through inhibition of AgRP/NPY neuron activity. PYY3-36 analogues like NN-1273, may possess significant therapeutic utility in the treatment of obesity.

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Hugh Piggins (Supervisor) & Simon Luckman (Supervisor)