Edited by Laszlo Nagy Keywords:Dietary fat Pro-opiomelanocortin b-Endorphin Opioid a b s t r a c tThe opioid system regulates food choice, consumption, and reinforcement processes, especially for palatable meals such as fatty food. b-Endorphin is known as an endogenous opioid peptide produced in neurons of the hypothalamus. In this study, we found that Intralipid (fat emulsion) ingestion increased c-fos expression in b-endorphin neurons. However, intragastric infusion of Intralipid only slightly increased c-fos expression 2 h after infusion. Further, dissection of glossopharyngeal nerve, innervating posterior tongue taste buds, partially but significantly decreased the Intralipid-induced c-fos expression. These results indicate that mainly the orosensory stimulation from fat may activate b-endorphin neurons, thereby promoting b-endorphin release.

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Rodents show a stronger preference for fat than sucrose, even if their diet is isocaloric. This implies that the preference mechanisms for fat and sucrose differ. To compare the contribution of the opioid system to the preference of fat and sucrose, we examined the effects of mu-, delta-, kappa-, and non-selective opioid receptor antagonists on the preference of sucrose and fat, assessed by a two-bottle choice test and a licking test, in mice naïve to sucrose and fat ingestion. Administration of non-selective and mu-selective opioid receptor antagonists more strongly inhibited the preference of fat than sucrose. While the preference of fat was reduced to the same level as water by the antagonist administration that of sucrose was still greater than water. Our results suggest that the preference of fat relies strongly on the opioid system, while that of sucrose is regulated by other mechanisms in addition to the opioid system.

Most animals, including humans, have a high avidity for consuming dietary fat. Previous studies have reported that fat preference can be attributed to many factors, including palatable flavor, texture, and chemical perception. Moreover, transection of nerves associated with either olfaction or gustation (i.e., olfactory or glossopharyngeal nerve) has been shown to decrease fat ingestion (1-3). In the central nervous system, several studies have suggested that the opioid system, canonically associated with reward circuitry, is associated with dietary preferences for fat. We recently reported that fat ingestion induces elevations in the endogenous opioid peptide, beta-endorphin, in cerebrospinal fluid (4). Furthermore, we have also demonstrated that fat ingestion can activate pro-opiomelanocortin (POMC) neurons in the hypothalamus, which synthesize beta-endorphin (5). Many reports have suggested that administration of opioid receptor antagonists can attenuate fat preference, an observation that is consistent with our findings (4,(6)(7)(8).A significant amount of experimental evidence implicates the opioid system in the reward and reinforcement of drug addiction. We previously demonstrated that, similar to drug administration, fat ingestion can serve as a reinforcer by inducing place preference or strong lever-pressing behavior in mice (we define these as "reinforcing effects") (9, 10). Moreover, it has been reported that opioid receptor antagonists can diminish the reinforcing influence of fat (11). These findings suggest that the opioid system contributes not only to fat preference, but also to reinforcement. However, the concentration of fat that produces a reinforcing effect might differ from that inducing preference behavior. Indeed, while mice prefer fat even at low concentrations (12), the reinforcing property of fat is only observed in response to substances with higher fat content (13). These findings indicate that the mechanisms underlying preference for fat are distinctly dependent on fat content. Since POMC neurons regulate energy homeostasis modulating feeding and/or energy expenditure (14-17), the opioid system might have an influence on the preference for high fat concentrations.It also seems likely that several nerves (i.e., the chorda tympani, glossopharyngeal, and trigeminal nerves) are involved in recognizing the presence of dietary fat in the oral cavity. In particular, the glossopharyngeal nerve contributes to preference behavior associated with high concentrations of fat, since glossopharyngeal nerve transection (GLX) can partially inhibit POMC neurons that have been activated by fat ingestion (5). Conversely, olfactory nerve transection (ONX) can abolish the preference for low fat concentrations (18); thus, olfactory and gustatory transduction related to fat preference might rely on fat concentration in a different manner. Summary High-fat foods tend to be palatable and can cause addiction in mice via a reinforcing effect. However, mice showed preference for low fat concentrations that do not...