Y eat?
Introduction
The importance of the hypothalamus in the regulation of food intake and energy balance has been established since experiments by Anand and Brobeck in 1940 [1]. These pioneers demonstrated that bilateral electrolytic lesions to the ventromedial nucleus (VMN) of the hypothalamus increased food intake and body weight gain leading to obesity, whereas lesions to the lateral hypothalamic area (LHA) decreased food intake, leading to body weight loss and even fatal starvation. This gave rise to the “dual-center hypothesis,” which proposed that the VMN and LHA serve as the satiety and feeding centers, respectively, in the brain [2]. We now understand that this model is overly simplistic, because significant roles for several other brain regions have also been demonstrated in the regulation of feeding behavior. These regions include the nucleus tractus solitarius (NTS) in the brainstem that mediates vagal afferent input regarding peripheral indicators of energy levels to the brain [3], [4]; the circumventricular organs, with nerve endings outside the blood-brain barrier and can thus be in direct contact with circulating energy balance-related factors [5]; the nucleus accumbens and ventral tegmental area that influence motivation- and reward-mediated feeding behavior; the amygdala that processes emotional and rewarding experiences associated with food; and various regions of the neocortex, which contribute higher information regarding taste, smell, and visual factors that affect food intake [6]. Nonetheless, the hypothalamus continues to be regarded as the main feeding center in the brain, because it can assess the immediate energy state of the organism and restore energy balance homeostasis. In addition to the VMN and LHA, the arcuate nucleus (ARC), dorsomedial medial nucleus (DMN), perifornical area (PFA), and paraventricular nucleus (PVN) of the hypothalamus are also strongly implicated in the maintenance of energy balance. Their neuronal signaling in central feeding circuits is chemically coded by several classes of neurotransmitters. These include the amino acid and amine transmitters, cytokines, cannabinoids, and most notably the neuropeptides. Chemical neurotransmission, including that of the peptides, can be characterized as being orexigenic or anorexigenic by stimulating or inhibiting food intake, respectively.
Neuropeptide Y (NPY) is one of the most abundant and most potent known orexigenic peptides found in the brain. It has been demonstrated to play a pivotal role in the control of food intake and body weight within the hypothalamus. Central administration of NPY by intracerebroventricular injection [7], [8] or its direct injection into specific hypothalamic sites, especially the PFA, PVN, and VMN [9], stimulates robust feeding responses in a dose-dependent manner. Chronic administration of NPY produces a sustained hyperphagia and increased body weight gain leading to obesity [10], [11]. In several models of animal obesity, the levels of NPY gene expression [12], [13], [14], [15], [16], [17] and NPY itself [18], [19] are increased. Similarly, increases in levels of NPY gene expression and peptide [20] precede hyperphagic behavior and are directly correlated with conditions of increased energy deprivation [21] and energy demand [22]. In effect, food deprivation is one of the most important factors that increase the expression of hypothalamic NPY. The NPY-mediated increase in food intake can be blocked by the application of NPY antagonists, particularly that after a period of fasting [23]. These studies have demonstrated that NPY administration is directly correlated with a state of positive energy balance.
Functional and behavioral approaches have provided compelling evidence for the orexigenic nature of NPY. However, they do not explore the mechanisms underlying the actions of NPY, which are just beginning to be understood. This review describes the cellular mechanisms engaged by NPY to modulate neuronal activity within hypothalamic feeding circuits. Specifically, 1) the conditions and factors that modulate the activity of neurons expressing NPY and 2) the direct and indirect effects of NPY release at the feeding-relevant hypothalamic nuclei are discussed.
Section snippets
ARC: Actions and modulations of NPY-expressing neurons
The central representation of the metabolic state is mediated in part by the levels of distinct circulating factors, including insulin, leptin, and ghrelin. The ARC is a prominent region in the hypothalamus for integrating these peripheral signals. This information is then relayed to various second-order hypothalamic targets. There are two distinct neuronal populations within the ARC that are considered to be critical in the regulation of energy balance. A subset of neurons located in the
NPY in DMN: Role in chronic disruption of energy balance
In obese animals such as the JCR:LA-cp rat [71], Otsuka Long-Evans Tokushima Fatty (OLETF) rat [72], lethal yellow (Ay) mouse [15], and MC4-receptor knockout mouse [15], NPY expression is induced in DMN neurons. Hyperphagia associated with chronic fasting [73] or sucking stimuli [74], [75] also induce NPY expression in the DMN. The elevation of DMN NPY gene expression is closely associated with melanocortin [76] and cholecystokinin (CCK) signaling [77]. α-Melanocyte-stimulating hormone (α-MSH)
NPY in VMN: Direct stimulation of feeding behavior
The VMN was one of the first hypothalamic nuclei implicated in the regulation of feeding. Microinjection of NPY directly into the VMN robustly increases food intake [9]. Whereas electrolytic lesions to the VMN produce a hyperphagic phenotype [80], electrical stimulation of VMN suppresses food intake [81]. This suggested that ongoing VMN activity exerts an anorexigenic tone. Y1 receptors are strongly expressed in the VMN [82] and activation of Y1 receptors inhibits the firing activity of VMN
NPY in LHA/PFA: Most potent site for NPY-mediated food intake
In contrast to the VMN, lesions to the LHA produced a hypophagic phenotype, suggesting that, in the intact animal, LHA activity stimulates food intake [2]. NPY elicited the strongest feeding response when it was administered to the perifornical region of the hypothalamus near the ventromedial edge of the fornix [9], [85]. This area is sparsely populated and NPY can induce a strong membrane hyperpolarization in some of these neurons (M. J. S. Chee and W. F. Colmers, unpublished observations).
NPY in PVN: Relevance of NPY signaling in development and adulthood
Strong feeding responses can also be elicited after the injection of NPY to the PVN [98]. The PVN receives dense NPYergic innervation [24], where these fibers are mainly derived from the ARC [99], [100]. Likewise, the PVN is also innervated by ARC POMC neurons. Fibers containing α-MSH are found in the same area but do not colocalize with the expression of NPY [100]. The relative proximity of melanocortin fibers to NPY projections allow melanocortins to functionally antagonize the effects of
Insight from genetic models
Despite the potent effect of NPY administration to stimulate food intake, the deletion of the NPY gene in an NPY knockout mouse does not result in a lean phenotype [105]. Similarly, germline knockout of the Y1[106], Y2[107], or Y5[108] receptors does not yield an obesity-resistant phenotype and none of these animal knockout models produced significant changes in body weight. However, different subtypes can operate together to have obesogenic or antiobesogenic effects. Double knockouts involving
Conclusion
The NPYergic signal (Fig. 1), including its expression, synaptic release, and receptor actions, is highly responsive to negative energy balance. The orexigenic NPY signal can suppress anorexigenic drive to restore energy balance homeostasis when energy levels are low, such as after food deprivation. The ARC contains the main site of NPY-expressing neurons in the hypothalamus. It contributes the main source of NPYergic innervation within the hypothalamus, although the NTS [114] also sends
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This work is funded by the Canadian Institute of Health Research (W.F.C.), the Queen Elizabeth II Graduate Scholarship (M.J.S.C.), and the Hotchkiss Brain Institute Obesity: A Brain Disorder Research Studentship (M.J.S.C.).