The Role of PrRP in Energy Balance

Abstract

Prolactin-releasing peptide (PrRP) is a neuropeptide expressed in the dorsomedial nucleus (DMN) of the hypothalamus, and in the nucleus of the solitary tract (NTS) and the ventrolateral medulla in the brainstem. Central administration of PrRP increases core body temperature and decreases food intake, but the role of endogenous PrRP in mediating such effects remains unknown. The overall aim of this thesis was to demonstrate critical functions for distinct PrRP neuronal populations in the regulation of energy balance. This was achieved largely by selective manipulation of gene expression in separate populations of PrRP neurons using Cre/Lox technology in transgenic mice. Two novel, conditional transgenic mouse models were characterised to investigate PrRP neurons. Expression of PrRP in the brain was required to regulate body weight and different aspects of energy balance. Specifically, hypothalamic PrRP neurons are first-order, leptin-sensitive neurons, which mediate the effects of leptin on thermogenesis and, to a lesser extent, food intake. In contrast, PrRP neurons in the brainstem, which do not express leptin receptor, mediate the satiating effects of CCK. In addition to thermogenesis and satiety, a role for NTS PrRP neurons in a gut-brain axis regulating post-prandial glucose homeostasis was investigated. Although central administration of PrRP had no effect on insulin release or hepatic glucose output, PrRP improved oral glucose tolerance indirectly by reducing gastric motility. Thus, PrRP signalling plays an important role in regulating multiple aspects of post-prandial homeostasis.Finally, virus-mediated gene delivery was employed to selectively activate or trace the projections from discrete populations of PrRP neuron. DMN or NTS PrRP neurons were activated selectively using pharmacogenetic "designer receptors". Activation of NTS PrRP neurons suppressed fast-induced food intake, further supporting a role for this population in mediating satiation. Using complementary anterograde and retrograde tracing techniques, the paraventricular nucleus of the hypothalamus was found to be a key target nucleus of PrRP projections from both the DMN and NTS, and is a likely candidate through which PrRP mediates its various effects on energy balance. Collectively, the data presented here demonstrate distinct functions for separate populations of PrRP neurons. Our studies provide a starting point for dissociating pathways involved in different aspects of energy balance. Although PrRP remains relatively little studied compared with other neuropeptides, PrRP neurons should be added as unique pieces to the distributed brain network affecting whole-body energy balance.

Date of Award	31 Dec 2016
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Catherine Lawrence (Supervisor) & Simon Luckman (Supervisor)