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  • Knowing that our strongest phenotypic differences between th

    2021-10-22

    Knowing that our strongest phenotypic differences between the genotypes involved feeding behavior in various contexts, we decided to examine the case of restricted feeding and food anticipatory activity. Animals faced with a restricted schedule of food availability develop a series of anticipatory behaviors and metabolic adaptations in order to prepare for the ingestion, b ng sale and metabolism of the contained nutrients [61]. In the rat and mouse strains commonly used in laboratory environments, this anticipation manifests in part as an increase in locomotion and circulating active ghrelin in the period immediately prior to scheduled meal presentation [16], [17], [18], [19]. These changes constitute a dramatic re-arrangement of the animal's normally nocturnal pattern of locomotion and ad libitum food intake. During the baseline period prior to food restriction, we found that FHH-GHSRm1/Mcwi rats moved significantly less over 24h than FHH-WT animals, with the greatest magnitude of difference being found during the dark phase of the light–dark cycle. Placing these animals onto a restricted feeding schedule resulted in a large reduction in spontaneous locomotion in FHH-WT animals, and a much smaller reduction in FHH-GHSRm1/Mcwi rats. As animals became accustomed to a timing of food presentation, their locomotion during the hours immediately preceding it rose. Activity in this period was significantly greater in FHH-WT rats, and this is consistent with a number of reports showing that ghrelin enhances food anticipatory activity [23], [62], [21], and that food anticipatory activity is attenuated in mice lacking the gene for either ghrelin or GHSR [24], [63], [23], [21] (but see [20]). However, the observed reduction in food anticipatory activity did not result in any relative impairments in food intake during the restricted feeding schedule. It may be that the reduced intake of the palatable, high-fat diet observed in FHH-GHSRm1/Mcwi rats is related to disrupted reward system functioning. Studies of palatable diet exposure and reward function in mice lacking functional ghrelin signaling support this conjecture [7], [64], [65], [66], [67]. However, in a situation where animals are not offered a choice in diet, such a hypothesis is difficult to address. To more directly assess the role of GHSR signaling in hedonic feeding, we designed a ‘dessert’ challenge modelled after one recently carried out in mice. In this study, mice engineered to lack the enzyme ghrelin O-acyltransferase (GOAT), the enzyme that octanoylates and activates the ghrelin peptide, were presented with a high fat diet in the last hour of a scheduled meal and ate significantly less of it than their wild-type counterparts [68]. Since in this model, the animals had been trained to meet their daily homeostatic caloric requirements within the limited period of food availability, their consumption of the palatable treat immediately following is analogous to a high-calorie dessert offered following a meal. We used a similar approach in our rat model of disrupted ghrelin signaling, and indeed our finding of reduced cookie dough consumption in FHH-GHSRm1/Mcwi rats is consistent with observations in mice by Davis et al. [68]. Our findings support the perspective that in the presence of palatable foods, ghrelin signaling can make sated animals behave as hungry ones [10], [69], [9], [70]. Together these data demonstrate that the FHH-GHSRm1/Mcwi rat does not respond to ghrelin, and in addition demonstrates a number of phenotypic effects in body weight, food intake, locomotor behavior, and gene expression that resemble, albeit in a generally milder form, the signature phenotypic markers of GHSR−/− mice (see Table 1). Of particular interest was our finding of reduced dessert consumption in FHH-GHSRm1/Mcwi rats, since this supports a role for ghrelin signaling in driving hedonic overconsumption of food, and points toward potentially useful future pharmacotherapies involving the ghrelin receptor. Studies such as this that demonstrate conserved functions of GHSR and ghrelin signaling are also of value from a comparative endocrinology standpoint. Because rats are often the preferred animal model for studying certain cognitive and behavioral tasks, reproductive behavior, and studies where repeated blood sampling or complex surgical procedures are needed, knowing that the FHH-GHSRm1/Mcwi rat approximates the GHSR−/− mouse in a number of ways constitutes an important piece of evidence justifying their validity in the study of ghrelin signaling in those fields.