Hunger and satiety: one brain for two?

UNDERSTANDING THE PHYSIOLOGICAL controls of eating and developing effective pharmacological tools to reduce eating has never been more important. The modern world faces an unprecedented obesity epidemic, and the current treatment strategies are rather unsuccessful. One possible solution may be a combination or cocktail therapy. Obesity control research has been more focused on “long-term” adiposity signals rather than the control of individual meals, which has been assumed to be rather plastic (34). Moreover, meal size appears to be under a confusingly large number of controls (27, 30, 33, 34). One potential reason for this is that avoiding excessive meal size may be very important physiologically because large meals are major physiological stresses (32) that, at some point, may be unadaptive. This suggests that the controls of meal size, including many controls of the gut-brain axis, may indeed be very potent and are likely to open efficacious therapeutic opportunities. A related reason not to underemphasize the potential of meal controls in obesity therapy is the increasing evidence that the weight regulatory system based on leptin, insulin, and other adiposity signals, in fact, seems more designed to stimulate eating and conserve energy when adiposity levels are too low rather than to inhibit eating and expend energy when adiposity increases (26). The consequences of the multifactorial and redundant controls of eating in animals and humans for potential pharmacotherapy are ambiguous. It may be that manipulations of individual signals will be ineffective because of functionally antagonistic, adaptive responses by other signals. However, the wealth of signals also creates the potential for therapies based on simultaneous manipulation of several signals. If many control signals operate simultaneously to control a single behavior, they must interact. This addresses an important point: is food intake truly a single behavior? Total food intake being composed of many individual meals is regulated by different control signals that govern meal initiation, the maintenance of eating through intrameal control mechanisms, meal-ending satiation, and intermeal satiety (e.g., see Ref. 28). Each one of these has to be considered a single behavior and their physiological controls may act independently. Therefore, signals that in pharmacological trials have been shown to interact, i.e., that 1) they produce a more potent effect on food intake than each signal alone or that 2) one of the signals reduces the effect of that induced by the other, may not necessarily interact under physiological conditions, especially if they govern different behaviors within the overall control of food intake. Therefore, one has to differentiate between physiological mechanistic interaction of controls and the effect of combination therapy in pharmacological trials that may only rely on a single measured outcome, i.e., food intake. Nevertheless, it seems very likely that combination therapies for obesity may have the same advantages of increased clinical potency and decreased side effects that have been demonstrated in many other areas of pharmacological therapeutics. Therefore, the study of interactions is an important area regarding their therapeutic potential. Basic research in this direction is relatively well advanced only in the case of CCK, which has been reported to functionally interact with several other peripheral signals that control eating, e.g., amylin, estradiol, gastric load, glucagon, leptin, and insulin (e.g., see Refs. 5, 6, 19, 22, and 34). With the exception of glucagon, all these interactions are synergistic, i.e., eating was further decreased when CCK and the other signal were applied simultaneously compared with CCK alone. Very much less is known about mechanistic vs. functional interactions. The synergistic interaction between CCK and amylin may reflect a necessary part of CCK signaling because 1) amylin antagonists attenuated CCK’s anorectic action in rats (17) and 2) the anorectic effect of CCK was almost completely abolished in the complete absence of endogenous amylin in knockout mice and was rescued by small doses of amylin (19). These mechanistic interactions are perhaps more relevant to physiology than to pharmacology. Insulin and leptin appear to act by increasing the sensitivity of the brain to CCK as meal-generated signals contributing to meal-ending satiation (21, 30, 33). Therefore, the integration of these messages within the brain including the signals reflecting body adiposity contributes to the sensation of satiation at meal termination. Theoretically, when an individual is underweight, the reduced adiposity signal allows larger meals to be consumed until weight is restored and vice versa. Over the last two years, the group by Hubert Mönnikes and colleagues published two interesting papers on the pharmacological interaction of the functional antagonist to leptin and insulin, i.e., ghrelin, with the satiating peptides CCK (9), bombesin (BB) and amylin (8). Kobelt et al. (9) found that subthreshold doses of CCK abolished the orexigenic effect of ghrelin when coadministered intraperitoneally. These experiments were complemented by immunohistochemical studies of expression of c-Fos protein. Ghrelin induced a strong increase in c-Fos expression in the hypothalamic arcuate (ARC) and paraventricular nuclei (PVN), but not in the nucleus of the solitary tract (NTS). CCK, on the other hand, induced c-Fos in the NTS and the PVN, but not in the ARC. CCK, however, completely reversed the ghrelin-induced c-Fos formation in the ARC. In the latest paper by Mönnikes and colleagues (Ref. 8), the authors extend their previous study on CCK and ghrelin to investigate now the possible interaction between BB and ghrelin, and amylin and ghrelin, respectively. Hence, this paper deals with an almost forgotten peptide because BB and its mammalian counterparts, gastrin-releasing peptide and neuromedin B, have not seen much interest over the last few years. One reason for this relative lack of interest may arise from some uncertainty about the true site of action (peripheral or Address for reprint requests and other correspondence: Institute of Veterinary Physiology and Center of Integrative Human Physiology, Univ. of Zurich, Winterthurerstrasse 260, 8057 Zurich, Switzerland (e-mail to tomlutz@ vetphys.unizh.ch). Am J Physiol Regul Integr Comp Physiol 291: R900–R902, 2006; doi:10.1152/ajpregu.00408.2006.