Molecular cloning techniques have recently led to the identification of a growing number of neuropeptide Y-receptor subtypes, suggesting possible subtype-specific involvement in different physiological processes. Here we report the first study which determines and compares the mRNA expression of all four cloned functional Y-receptor subtypes (Y1, Y2, Y4 and Y5) in consecutive sections of the rat brain on a cellular level, using a uniform in situ hybridization technique. Our results demonstrate that Y-receptor subtype mRNA expression is widely distributed throughout the rat brain. Interestingly, coexpression of all four Y-receptors, at different levels, is particularly evident within the limbic system, including the hypothalamus, hippocampus, amygdala, piriform and cingulate cortices and tegmental areas, all of which are heavily involved in behaviour, emotion and homeostatic regulation. Particularly interesting is the demonstration that Y5-receptor mRNA expression always coincides with the presence of Y1-receptor mRNA (although not vice versa), possibly due to the overlapping organization and transcriptional control of their genes. However, it is also clear that several brain nuclei display preferential expression of one or a selective combination of Y-receptor subtype mRNAs. Furthermore, it is evident that there is regionalization of expression within certain loci which express all four receptor subtype mRNAs, particularly within the paraventricular and arcuate hypothalamic nuclei. Our results suggest that some of neuropeptide Y's (NPY) effects may be mediated through one particular subtype, whereas other physiological processes might require the coordinated action of different subtypes within the same or discrete areas.

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IntroductionObesity, which is an important risk factor for serious chronic illnesses such as insulin resistance, type 2 diabetes, and heart disease is caused by an imbalance between energy intake and energy expenditure. There are numerous factors influencing whole-body energy balance, including neural and hormonal signals, which, when altered could result in obesity. It is becoming increasingly evident that the central nervous system, particularly the hypothalamus, plays a critical role in integrating these signals to regulate energy balance and that neuropeptide Y (NPY) is an important neuromodulator in this system (1, 2).NPY is widely distributed throughout the brain (3). However, most of the metabolic actions of NPY appear to be mediated through defined hypothalamic nuclei, including the arcuate nucleus (Arc) where numerous NPY-containing neurons originate, the paraventricular nucleus (PVN), where many NPYcontaining arcuate neuron terminals and NPY-binding sites are located, and the ventromedial hypothalamic (VMH) nucleus, which has been referred to as "the satiety center" (3, 4). NPY is the most potent orexigenic agent known (5, 6) and can also cause changes in circulating hormone levels (7). Chronic intracerebroventricular (icv) administration of NPY results in hyperphagia, hyperinsulinemia, insulin resistance, and obesity (8-10). Lesions of the VMH in rodents also cause multiple changes in metabolic status, including hyperphagia, hyperglycemia, and hyperinsulinemia (11). Interestingly, injection of NPY directly into the VMH significantly increases food intake (12), and NPY-induced feeding is enhanced in VMH-lesioned rats (13). These data suggest the VMH may also be a site of action for NPY in the development of obesity; however, the mechanisms by which NPY is involved in each aspect of central energy regulation remain to be defined.Much research has focused on which of the 5 NPYreceptor subtypes cloned so far (Y 1 , Y 2 , Y 4 , Y 5 , and the y6) (14) might mediate the potent NPY-induced feeding response. Several lines of evidence point to the Y 1 -and/or Y 5 -receptor subtypes being the most likely candidates for such an action (15-19). In addition, our previous studies investigating the mRNA expression of all known Y receptors in the rat brain also show clearly that both Y 1 -and Y 5 -receptor subtype mRNAs are expressed in areas pivotal in regulating energy balance (20).Glucocorticoid hormones play a critical role in energy balance and also appear to mediate at least some of their actions through the central NPY axis Chronic central administration of neuropeptide Y (NPY) causes hyperphagia, hyperinsulinemia, and obesity, a response that is prevented by prior adrenalectomy (ADX) in rats. The basis of NPY's effect and how the acute responses to this peptide are affected by ADX remain unknown. This study investigates the role of glucocorticoids in acute NPY-stimulated food intake, acute NPY-induced insulin release, and hypothalamic NPY-receptor mRNA expression levels. NPYinduced food intake was similar in A...

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