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  • br Methods br Results br Discussion In

    2021-09-23


    Methods
    Results
    Discussion In this series of studies we hypothesized that FHH-GHSRm1/Mcwi rats would, relative to their WT counterparts, exhibit a metabolic and behavioral phenotype reminiscent of GHSR−/− mice. Through the use of the GHSR−/− mouse, a great deal about the role of ghrelin signaling in metabolism, behavior, and even cognition has been learned in recent years. One of the most important, and earliest findings regarding the GHSR−/− mouse was that it shows reduced weight gain when placed on a high-fat diet [37]. We did not observe this characteristic in our rats, as animals of both genotypes gained equivalent amounts of weight, and did so at equivalent rates. A similar pattern of diet-induced weight gain was observed in congenic GHSR−/− mice, suggesting that the effect of GHSR ablation on diet-induced obesity depends in part on an interaction with the genetic background of the subject [42]. When considering the lack of effects of our GHSR mutation on body weight, body composition, and CAY10683 mg tolerance, it should be noted that in our hands, neither of the genotypes gained more than approximately 20% of its baseline body weight, nor did any rats develop fasting hyperglycemia or hyperinsulinemia, even after 12weeks of HFD exposure. Given this, it may be that the FHH strain is inherently resistant to diet-induced obesity and type-II diabetes. If this is the case, then it would be difficult to ascertain a role for GHSR signaling in ‘resisting’ these effects, given that in the FHH strain, there is nothing to be resisted. The choice of background strain in rodent studies inevitably presents challenges, as each strain possesses its own pre-existing traits against which the effects of genetic mutations must be compared. This is true of the FHH strain, which exhibits a number of important physiological and behavioral traits that set it apart from outbred strains that are more commonly used in behavioral and neurometabolic studies. Aside from their comparatively short lifespan (11–13months) and tendency to develop spontaneous hypertension and renal disease in adulthood [43], FHH rats demonstrate increased preference for alcohol [44], more depressive-like behavior [44], [45], and higher levels of social anxiety [46] than outbred strains. These rats also exhibit regionally-specific alterations in 5-HT turnover [47], blunted cocaine-induced striatal DA release [48], and a blunted behavioral response to serotonergic agents [49]. Relative to Wistar and Sprague–Dawley rats, FHH rats exhibit higher levels of spontaneous locomotion [50], eat less when faced with restricted food access [51], and gain less weight when stressed [49]. Many of these strain differences are in precisely the variables of most interest to the metabolic and neuropsychiatric models commonly employed in ghrelin studies, and thus FHH-specific strain effects must be accounted for when designing experiments. This highlights the broader implications of background strain control when using transgenic animals. A pertinent example of this from the mouse literature is the issue of body weight in GHSR−/− mice, with some knockouts showing no difference in baseline body weight compared to wild-types [37], but knockouts thoroughly backcrossed onto a C57BL/6J line being reliably lighter than wild-types [42]. Both ghrelin and GHSR1a are expressed in pancreatic islet cells, and ghrelin acting on β-cells in either a paracrine or endocrine capacity tends to reduce glucose-stimulated insulin secretion [52], [53], [54], though this is not always observed in every model and dose [55]. Given this, and given the fact that GHSR−/− mice are reported to have improved insulin sensitivity relative to WT animals [36], we hypothesized that our FHH-GHSRm1/Mcwi rats would show improved glucose tolerance. Surprisingly this was not the case, as FHH-GHSRm1/Mcwi rats did not differ statistically from FHH-WT rats at any timepoint during the glucose tolerance test, in fact they showed a tendency toward impaired glucose tolerance, though this was not statistically significant. Fasting blood glucose collected prior to the GTT and at sacrifice did not differ between the genotypes, and unlike GHSR−/− mice that normally show reduced serum insulin in adulthood [37], [36], fasting insulin collected at sacrifice was not different between our genotypes.