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Department of Clinical Biochemistry Cambridge Institute for Medical Research Addenbrooke’s Hospital Cambridge CB2 2XY, United Kingdom
Address all correspondence and requests for reprints to: Stephen O’Rahilly, University Departments of Medicine and Clinical Biochemistry, Box 232, Addenbrooke’s Hospital, Cambridge CB2 2QR, United Kingdom. E-mail: sorahill{at}hgmp.mrc.ac.uk.
We are in the midst of an obesity epidemic with major health and economic challenges facing the developed world. Fortunately, this crisis has been accompanied by remarkable progress toward identifying and understanding the homeostatic mechanisms that underlie energy balance. Major research efforts have identified a highly complex physiological system, in which peripheral hormones communicate information regarding the energy status of an organism to central pathways that influence food intake and energy expenditure. Leptin and insulin, for example, are both recognized as playing key roles in conveying information about the long-term status of peripheral energy stores to the central nervous system (1).
There is also an increasing recognition of the importance of more rapidly responsive lines of communication linking directly the food we eat to key appetite centers. So-called satiety signals are released from the gut in response to nutrient ingestion and act within the hypothalamus or brain stem to limit the duration of individual feeding episodes. The classic example of such a signal is cholecystokinin (CCK), a gut peptide released into the circulation in response to fatty acids. CCK acts at receptors on peripheral vagal afferent terminals and information is relayed on to appetite centers within the brain stem nucleus of the solitary tract (NTS) (2).
Peptide YY (PYY) is a 36-amino-acid peptide secreted from the endocrine L cells of the gut (3). It is found at low levels in the small intestine with concentrations increasing distally throughout the gut to reach maximum concentration in the rectum. Circulating PYY levels are low in the fasting state and rapidly increase postprandially when two forms, PYY1–36 and PYY3–36, are released into the circulation. Both peptides have local effects on gut motility and, rather confusingly, both have the ability to increase food intake if administered directly into the cerebrospinal fluid of animals (4). In contrast, it has been known for over a decade that peripherally administered PYY3–36 can actually reduce food intake (5). A mechanistic basis for this effect has remained largely elusive until recently, when data from the Bloom laboratory reignited interest in PYY3–36 (6, 7).
Using a combination of rodent models and human clinical studies, Batterham and colleagues (6, 7) have recently proposed an elegant model for PYY3–36-induced satiety. These investigators demonstrated that peripherally administered PYY3–36 suppressed food intake in rodents for 4 h after a single dose. Similarly, after a period of fasting, a single infusion of PYY3–36 was capable of reducing food intake by over a third in both lean and obese human volunteers for 24 h (6). Finally, and most provocatively, circulating levels of PYY3–36 were found to be lower in obese subjects, implicating PYY3–36 deficiency as being involved in the pathogenesis of human obesity (7).
Direct evidence that PYY3–36 is acting at the level of the hypothalamus comes from immunohistochemical studies that demonstrated that peripherally administered PYY3–36 induced c-Fos expression (a marker of neuronal activation) in arcuate neurons expressing proopiomelanocortin (POMC). POMC is the precursor peptide from which the anorexigenic peptide 
-MSH is derived. The notion that POMC neurons were the downstream targets of PYY3–36 was strengthened through electrophysiological studies demonstrating that PYY3–36 was inhibitory to another population of neurons within the arcuate, those expressing the orexigen neuropeptide Y (NPY). Not only do this population of NPY neurons exert a tonic inhibition upon POMC neurons, they also abundantly express the presynaptic autoinhibitory Y2 receptor (Y2-R). PYY3–36 acts as an agonist at the Y2-R on NPY neurons and in doing so the result is removal of the tonic inhibition on adjacent POMC neurons. The observation that the ability of PYY3–36 to reduce food intake is not seen in Y2-R knockout mice strengthens this model.
Furthermore, Batterham et al. (6) argue that the reason for the discrepancy between the orexigenic effects of central PYY3–36 administration vs. the anorexigenic effects of peripherally delivered peptide lies in the fact that the latter results only in activation of the Y2-R in the hypothalamic arcuate nucleus. This is an area where the blood brain barrier is relatively permeable and so has direct access to circulating hormones. This anatomical specificity was confirmed by centrally administering a potent Y2-R agonist. Delivery directly into the arcuate dose-dependently inhibited food intake in an identical way to PYY3–36, whereas injection of the same agonist into the paraventricular nucleus, an area of the hypothalamus unable to directly communicate with circulating signals, did not alter food intake.
Thus, it appears that, like leptin (1), the appetite-suppressing effects of PYY3–36 are mediated through the activation of arcuate POMC neurons of the central melanocortin system.
Subsequent studies have raised some questions regarding the precise conditions under which PYY3–36 works to suppress food intake and the likely duration of such an effect (8, 9). In addition, despite the evidence implicating hypothalamic POMC neurons as a target for PYY3–36, it remains unclear as to whether interactions at this site are responsible for all of the appetite-suppressing effects seen. For example, PYY3–36 could also act at the brainstem, an established target for a number of anorexigenic gut peptides, or indeed upon the gut itself to reduce food intake.
In this issue of Endocrinology, Halatchev et al. (10) report some insightful observations that challenge us to re-evaluate the current model of how PYY3–36 induces satiety. They clearly demonstrate in fasted wild-type mice that a single dose of PYY3–36 has a potent anorexigenic effect, reducing food intake by more than a third over a 3- to 4-h period. Importantly, this report also demonstrates that PYY3–36 is equally effective in reducing food intake in freely feeding mice during the more physiologically relevant dark cycle. Intriguingly, the key to reproducibly replicating the appetite suppressing effects of PYY3–36—both in fasted or ad libitum-fed mice—was to thoroughly acclimatize mice to handling and ip injections. No effects were seen in mice that were not thus acclimatized.
Halatchev et al. (10) also re-examined the role the central melanocortin system may have in inducing satiety after peripheral PYY3–36. Consistent with previous reports, the authors found an increase in c-Fos expression within arcuate POMC neurons. However, no such increase was seen within POMC neurons of the NTS. The lack of activation in brain stem satiety centers is striking, given that CCK, which has an anorexigenic effect similar to PYY3–36 in terms of magnitude and duration, is capable of substantially inducing c-Fos activation in POMC neurons within the NTS (2). They went on to study the effects of PYY3–36 in melanocortin 4 receptor knockout [Mc4r–/–] mice, a well-established model of disrupted central melanocortin signaling. Unexpectedly, Mc4r–/– mice were completely sensitive to the anorexigenic effects of PYY3–36. We have recently studied the effects of PYY3–36 on feeding behavior in Pomc null mice, which lack all melanocortin ligands (11). Consistent with the data presented in this issue of Endocrinology, the short-term anorexigenic effect of PYY3–36 was also retained in Pomc–/– mice. Thus, data from two independent models, one lacking receptor (MC4R) the other ligand (-MSH), concur that an intact central melanocortin system is not required for the anorexigenic effects of PYY3–36.
Given the data collected thus far, where might PYY3–36 be acting? Although electrophysiological (12) and immunohistochemical data identified POMC neurons as downstream targets of PYY3–36, this does not necessary imply that POMC peptides are critically involved in the anorectic response. For example, POMC arcuate neurons coexpress cocaine- and amphetamine-regulated transcript (CART), another potent appetite suppressing peptide (13). Although a receptor for CART has not been identified and its downstream targets remain elusive, it is feasible that CART peptides may mediate the effects of PYY3–36 on feeding behavior. To this end, peripheral administration of PYY3–36 to Cart-deficient mice (14) would be a worthwhile undertaking. Furthermore, we also know that POMC neurons release 
-aminobutyric acid (15), and it may be that this neurotransmitter could influence synaptic transmission to downstream neurons in response to circulating plasma levels of PYY3–36.
Of course, rather than an increase in the activity of appetite-suppressing peptides, the effects seen with PYY3–36 may also be explained by a decrease in the activity of appetite-stimulating hormones. Certainly, NPY mRNA expression levels are reduced after peripheral PYY3–36 administration (6, 9). Thus, inhibition of NPY neurons alone may explain reduction in food intake after PYY3–36 treatment with the observed effects in adjacent POMC neurons merely representing a physiologically insignificant epiphenomenon of reduced NPY neuronal activity. If this were true, then one would expect that Npy–/– mice (16) would resemble Y2-R-deficient mice in their resistance to the anorectic effects of PYY3–36.
Intriguingly, the key to reproducibly replicating the appetite suppressing effects of PYY3–36—both in fasted or ad libitum-fed mice—was to thoroughly acclimatize mice to handling and ip injections. No effects were seen in mice that were not thus acclimatized. This finding raises questions about the physiological relevance of PYY3–36 in appetite control outside the relatively comfortable setting of the laboratory. Acclimatization in an unheated, food-depleted, feline-filled real world is somewhat harder to achieve. The most obvious candidates for the inhibitory effect of real life on PYY action are adrenally derived glucocorticoids and catecholamines. However, it is noticeable that fasting, which increases corticosterone levels in mice, does not preclude the anorexigenic effect of PYY3–36 once the necessary acclimatization has been carried out. Quite what aspect of the stress response it is that inhibits the action of PYY3–36 is unclear.
Finally, providing that PYY3–36 can help reduce food intake, does it really matter if we don’t know exactly how it works? There are many clinically useful drugs whose mechanisms of action remain unclear. For example, metformin has proven efficacy in the treatment of type 2 diabetes mellitus in those who are overweight, yet its precise site of action is still hotly debated. Nevertheless, a mechanistic basis of action is still worthwhile pursuing because it may unveil novel ways into a system that, for very good reasons, is layered with complexity. Continued insights into mechanisms of action from pharmacological and rodent studies will continue to test our current working models. If what we find does not easily sit with the status quo, the real challenge lies in the ability to think laterally and remodel the template. Further studies into the biology of PYY3–36 may well provide an opportunity for trailblazing novel and potentially therapeutically relevant pathways that as yet remain untapped.
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Received March 16, 2004.
Accepted for publication March 17, 2004.
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