the early days of the discovery and identification of different forms of CCK in the GI tract and the abdominal vagus (20), on the one hand, and in the central nervous system (CNS; 7, 17), on the other hand, might have already anticipated important roles of the peptide in various aspects of energy homeostasis, ranging from regulation of feeding behavior and body mass to body temperature control. Indeed, centrally or peripherally administered CCK has proven to be a satiety agent in animal experiments (10) and, as such, this peptide or some of its derivatives have raised hopes of representing an effective candidate of a genuine antiobesity medicine for humans. The CCK peptide family has been characterized in the literature as consisting of two receptor sets, forming a more comprehensive picture of the mechanisms of their action. The availability of specific antagonists for these two receptors, now called CCK1 and CCK2 receptors—corresponding to the peripheral type and central type receptors, respectively—and some more-or-less selectively acting agonists, offered means to study various aspects of energetics. As a result of these developments, the relatively long history of the function of CCK-ergic system in satiety has gradually become straightforward: as supported by experiments carried out in rats on the satiety action of the peptide, CCK1 receptors now appear indispensable (19, 24), while the CCK2 receptors do not take part in this regulation.
Interest in the regulation of body temperature, another aspect of energetics in animals, used to be less intensive in investigations on CCK-dependent functions. In particular, the first data indicated a monotonous CCK-induced hypothermia in rats (22) and were later supported by several authors showing a robust dose-dependent hypothermia (14, 15, 38). Even central administration of CCK-octapeptide was reported to result in hypothermia that was also accompanied by thermoregulatory effector responses known to contribute to decreases of core temperature (18). Although the mechanism of hypothermic action of CCK peptides was still unknown in the 1980s, this thermoregulatory effect seemed to have fitted well into a general negative imbalance of energetics, which also included decreased energy (food) intake, thus leading to a slowing down of general metabolism (regarded as a coordinated response to conserve energy). However, some published research showed slight rises of body core temperature in some species after central administration of CCK (8, 13). In fact, through applying more controlled experimental conditions and antagonists to the two CCK receptors, it could be shown that in rats exposed to a range of ambient temperature, an intracerebroventricular microinjection of CCK-8 led to a rise in core temperature that resembled the fever response induced by the established pyrogen mediator, PGE (33). Furthermore, pretreating rats with the CCK2 receptor antagonist L365,260 given either peripherally or centrally could attenuate that feverlike response, while the CCK1-receptor antagonist devazepide—otherwise able to antagonize the hypothermic effect of a large dose of CCK-8 given peripherally—failed to attenuate the fever response to intracerebroventricular CCK-8. Similar results were later reported by other authors (9, 31), showing also a dose dependency of the size of CCK-induced fever.
A rise in core temperature, however, cannot necessarily be regarded as a fever, unless it is accompanied by appropriate thermoregulatory changes, such as a rise in heat production and evidence for decreased heat loss (33) and other, nonthermoregulatory changes as components of the sickness behavior, the latter resulting from efferents from some CNS areas and leading to a coordinated set of symptoms (11). The development of two or more of the established components of the sickness behavior (e.g., inactivity, anorexia, sleepiness, social isolation, decreased grooming behavior), together with a rise in body core temperature is regarded as a strong argument for a febrile nature of the response, whereas a rise of core temperature alone may also be a simple passive hyperthermia. In the latter case, thermoregulatory compensations (i.e., skin vasodilatation, signs of increased evaporation aiming at increasing heat loss) are evoked in defense of normothermia, just the opposite of what can be observed during genuine fever (vasoconstriction, shivering, etc.).
The role of a CCK-ergic mechanism in fever could be clarified further by using the established LPS fever model (25) to see whether specific antagonists could modify that response. In fact, an attempt in this direction was published showing that a CCK2-receptor antagonist was able to attenuate at least the first phase of LPS fever in rats ( 32 ). Availabilty of genetically modified mice and rats lacking or overexpressing receptor(s) of CCK has improved our understanding about functional aspects of biologically active peptides. In this line, experiments using mice lacking the CCK2 receptor indicated a minor but significant role of that receptor in normal thermoregulation (36).
In this issue of the American Journal of Physiology—Regulatory, Integrative, and Comparative Physiology, data have been published of detailed analysis of fever response observed in three different doses of LPS in mice lacking functional CCK2 receptors and in their wild-type counterparts (37). According to the study's results, which were carried out using biotelemetry, all parameters of sickness behavior monitored (decreases in activity, body weight, and food intake, as well as the rise of body core temperature), showed reduced response to 500 or 2,500 μg/kg intraperitoneal injection of Escherichia coli LPS compared with the same responses of wild-type mice. As emphasized by these authors, their results do not exclude the role of vagal afferents in the initiation of the fever responses observed, but the parallel changes of fever with all three parameters of sickness behavior monitored having been attenuated in CCK2 receptor knockout mice, furnishing new evidence for the complex initiation of an immune system-brain communication, at least partly mediated by a CCK2 receptor-associated mechanism. In fact, using a different experimental paradigm (intracerebroventricular infusions of PGE1 or CCK-8 in normal rats studied also by biotelemetry), we (34) observed that dose-dependent fevers accompanied by decreased activity.
Indirect evidence for the participation of CCK2 receptors in fever response was obtained in experiments using rats that lack functional CCK1-receptors, the Otsuka Long-Evans Tokushima fatty (OLETF) rats (12), compared with normal rats (members of the mutant strain), showed an enhanced febrile response to an LPS challenge, a phenomenon explained by a CCK2 receptor activity supposed to be unopposed by CCK1 receptors. It remains to be seen, however, to what extent data obtained from experiments on genetically modified mice could be supported by similar results observed in other species. At least for the role of CCK-ergic mechanisms in satiety, it was shown that OLETF rats exhibit the expected hyperphagia with the development of obesity, but CCK1 receptor null mice (not possessing functional CCK1) failed to develop the same positive energy balance (2).
As discussed already before, CCK2-receptor knockout mice showed only minor changes in normal thermoregulation such as basal core temperature or circadian amplitude of core body temperature (36), while OLETF rats showed more robust differences in cold defense compared with normal rats (23, 29). In this connection, it would be interesting to learn whether LPS-induced fever could be similarly augmented in CCK1-KO mice, as has been observed in OLETF rats. Another thermoregulatory comparison between this mouse and rat strain could be the study of the size of CCK-induced fever on intracerebroventricular microinjection or infusion of the mixed CCK1/CCK2 receptor agonist CCK-8.
To make a strong case for the possible role of CCK-ergic mediation in fever of infection, still further parameters should be sought that may complement the full scale of sickness behavior. One candidate symptom for such a role could be behavioral depression or malaise, as suggested originally by Hart (11) and extended by several authors, in general (3, 4), and discussed in detail in connection with cytokines (6). More recent evidence for the extended list of sickness behavioral symptoms, including anxiety and depression, has been published even in IL-6-deficient mice (30), while evidence was found for the possible importance of CCK2 receptors in anxiety-like behaviors (5, 35) and in anxiety-induced hyperalgesia in rats (1).
To clarify the possible role of CCK-ergic mechanisms in energetics (i.e., fever or hypothermia), some other, seemingly unrelated effects of the peptide may also be discussed. The established hypothermia-inducing effects of peripherally administered CCK—supposed to be mediated by CCK1 receptors (33)—appear to be supported by recent studies (26, 28). The latter authors have shown dose-dependent inhibition of presympathetic vasomotor neuronal discharge, allowing peripheral vasodilatation (hence hypothermia) and a CCK1-receptor-mediated bradycardia not found in OLETF rats otherwise developing on peripheral administration of CCK-8 (16). On the other side of the coin (i.e., for the possible role of CCK2 receptors in fever-related events) is evidence that the development of anxiety in mice depends on the presence of CCK2 receptors (5), and cerebral vasodilatation is probably necessary for the central effects of the peptide, for the neuronal changes in panic is also mediated by CCK2 receptors (27). In fact, it has been previously shown that increased hypothalamic metabolic activity (and possibly blood flow) may be a prerequisite for the centrally coordinated heat-gaining responses that occur during fever (21).
All in all, the present short summary has focused on current available data that indicate differential effects of CCK-ergic mechanisms in animal energetics, in general, and in thermoregulation, in particular. Accordingly, CCK1 receptors mediate satiation and hypothermia, the latter probably via increased heat loss and/or decreased heat production. Another thermoregulatory effect mediated by neuronal CCK could be a fever response, in which CCK2 receptors appear to play a role. Further studies are needed to learn more on the relationship between the central CCK-ergic thermoregulatory mediation with other established fever mediators such as cytokines or PGE. The possible importance of CCK-ergic mechanisms in normal thermoregulation cannot be judged on the basis of limited experimental evidence available at present.
- Copyright © 2007 the American Physiological Society