Neuropeptide Y

Neuropeptide Y is the pivotal hormone in the regulation of food intake and energy balance – Discuss.

1. Neuropeptide Y and the hypothalamus

Neuropeptide Y (NPY) is the most profoundly orexigenic compound identified to date [1]. It is abundantly expressed in several central nervous system regions, including the hypothalamus [2, 3]. The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Neuropeptide Y was first reported as a peptide abundant in brain tissue in 1982 [4], and has since been extensively implicated as a pivotal component of neurocircuitry subserving energy balance. During the period since its isolation, emphasis has moved away from clear cut and perhaps oversimplified anatomical divisions of feeding and satiety centres toward a description of the specific neurotransmitters that modulate feeding behaviour and energy expenditure.

1.1 NPY and its receptors

NPY exerts most of its biological effects through five G-protein coupled receptors termed Y1, Y2, Y4, Y5 and y6 that mediate either inhibition of adenylate cyclase or increases in intracellular calcium. A sixth receptor, Y3 is yet to be cloned, however it has been found to be truncated and inactive in rat and man [5]. The balance of evidence favours the Y1 and Y5 receptors as playing predominant role as they mediate the hyperphagic and obesity-promoting effects of NPY.

The Y1 receptor was the first Y-receptor to be cloned [6]. In animals maintained on a single mixed diet, NPY has been found to act primarily via Y1 receptors to potentiate food intake [7, 8]. Further evidence indicates that a Y1 receptor agonist has a selective stimulatory effect on carbohydrate intake [9], suggesting that Y1 receptors are critical for the carbohydrate stimulatory action of NPY.

The Y5 receptor is expressed at relatively high levels in the lateral hypothalamic area, close to the site where NPY acts most potently to stimulate feeding [10]. NPY receptor density in this area is decreased during starvation, which may be explained by down regulation of these receptors following increased local availability of NPY [11]. Synthetic high affinity Y5 antagonists have been used efficiently in determining both spontaneous feeding and the hyperphagia induced by central injection of exogenous NPY [12], illustrating the importance of NPY in modulating feeding behaviour.

1.2 Distribution of NPY

Since the discovery of NPY neurones and their axonal projections, a robust body of literature has developed around the potential functions of this peptide. Forty percent of NPY is synthesized in the arcuate nucleus [2]. At this site, NPY is contained within neurones in the medial aspect of the nucleus, and is colocalised with another orexigenic peptide, agouti-related peptide (AgRP) [13]. The actions of this pairing of orexigenic peptides is counterbalanced by neighbouring neurones in the same nucleus, which contain anorexigenic peptides pro-opiomelanocortin (POMC) and cocaine and amphetamine regulating transcript (CART). Leptin receptors are present on both of these neuronal types, and the adipocyte-derived peptide, leptin, acts to inhibit NPY/AgRP neurones and to POMC/CART neurones consistent with its role in reducing food intake [14].

NPY is also synthesized in the dorsovagal complex of the medulla, which receives afferent nerves from the gastrointestinal tract. NPY neurones from both sites project to the paraventricular nucleus, ventromedial hypothalamus and perifornical area/lateral hypothalamus [2, 15, 16]. The paraventricular nucleus is the most sensitive site for NPY-induced eating [17].

2. NPY knockouts

The era of knockout mice in the NPY field was started by Erickson and colleagues in 1996 with the generation of a NPY knockout mouse line [18]. Initial studies on the NPY knockout mice did not show a reduction in food intake or body weight under normal conditions, although they did show hyperphagic behaviour after fasting [18]. Furthermore, interventions such as high fat diet did not appear to influence body weight or food intake in the NPY knockout mice [19]. Interestingly however, although the high fat diet increases the weight of their fat pad depot in the NPY knockout mice, the actual body weight of these mice was not significantly different from the chow fed controls [19]. In response to NPY deficiency, there is an increase in the synthesis and secretion of AgRP [20], suggesting that unique adaptations to NPY deficiency are capable of functionally compensating for the absence of this peptide, resulting in limited changes to body weight and food intake.

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