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  • It was recently reported that aged GHSR mice in addition

    2022-06-22

    It was Phosphatase Inhibitor Cocktail 3 (100X in DMSO) recently reported that aged GHSR−/− mice, in addition to showing alterations in meal pattern microstructure, exhibit NPY and AgRP mRNA upregulation in the ARC [56]. After an overnight fast, our animals exhibited a similar pattern of upregulated NPY and AgRP mRNA expression. Given that GHSR1a is expressed on NPY/AgRP neurons in the ARC, and that ghrelin administration tends to increase the expression of these neuropeptides [31], [32], finding NPY and AgRP upregulation in animals lacking GHSR signaling is somewhat paradoxical, particularly in light of our finding of reduced refeeding in FHH-GHSRm1/Mcwi rats. There are two factors that may have contributed to this effect. Diet-induced obese animals are known to have attenuated central responses to ghrelin, with reductions in ghrelin-induced NPY and AgRP transcription, cFOS induction in NPY and AgRP neurons, and food intake relative to chow-fed animals [57]. Since our rats had been on a high-fat diet for 12weeks, it is possible that FHH-WT rats had developed some degree of central ghrelin resistance, limiting its ability to upregulate NPY and AgRP expression. In addition, fasting leptin levels were reduced, albeit non-significantly, in our FHH-GHSRm1/Mcwi rats relative to FHH-WTs, and this may favor orexigenic gene expression [58]. In combination, these two factors may have contributed to increased fasting orexigenic neuropeptide gene expression in our FHH-GHSRm1/Mcwi rats relative to FHH-WT rats. In Phosphatase Inhibitor Cocktail 3 (100X in DMSO) to the lack of effect of our GHSR mutation on body weight and glucose homeostasis, FHH-GHSRm1/Mcwi rats did show a number of differences in feeding behavior. Ghrelin levels rise under fasting conditions and play a role in driving food-seeking and consummatory behavior [3], [4], and because of this we hypothesized that rats without functioning ghrelin signaling would be deficient in these capacities. To begin to test this, we decided to examine rebound feeding after an overnight fast. Mice given GHSR antagonists directly into the ventral tegmental area (VTA), a key structure in the mesocorticolimbic dopamine system, show blunted rebound feeding [7], however global GHSR−/− models show normal refeeding [59], [42]. As with GHSR−/− mice, our FHH-GHSRm1/Mcwi rats did not show increased food consumption relative to wild-types during the first 6h of food access. However, when food intake over the entire 24h period following food presentation was considered, we found that FHH-GHSRm1/Mcwi rats ate less than wild-types. This may point to an altered response to satiety signals in FHH-GHSRm1/Mcwi rats, given that the difference in food intake presumably emerges some time after the initial bout of hyperphagia following food return. Ghrelin signaling is important in mediating dietary preferences when food choice is available, biasing animals toward palatable, high-calorie diets [60]. We approached the question of palatable, high-calorie diets first by observing food intake and body weight while animals consumed a high-fat diet. Initially, we hypothesized that FHH-GHSRm1/Mcwi rats would consume less of a provided high-fat diet compared to wild-type rats. This did appear to be the case, because when calorie intake over the period of HFD exposure was viewed as a whole, FHH-GHSRm1/Mcwi rats consumed significantly less than FHH-WTs, though this effect was the strongest during the first two weeks of HFD exposure. The tendency to eat less when given an HFD is consistent with observations in GHSR−/− mice, which also tend to eat less than wild-types on a high-fat diet [37], [42], [36]. Since we did not offer our animals a choice of diet in this study, it is uncertain whether our observations reflect an alteration in the homeostatic regulation of caloric intake, or the absence of a hedonic response to a palatable, high energy diet. Interestingly, despite consuming fewer calories on average during the period of HFD exposure, FHH-GHSRm1/Mcwi rats gained weight at the same rate as FHH-WTs, suggesting that increased feed efficiency may be a unique feature in our model. While we were unable to measure energy expenditure directly, the argument for increased feed efficiency is supported by our finding that FHH-GHSRm1/Mcwi rats exhibit significantly reduced home-cage locomotor activity, and this suggests reduced energy expenditure, which could account for the difference in feed efficiency during the dynamic period of HFD-induced weight gain.