During the present reporting period, our research in this area was limited due to severe reductions in available research resources. Nevertheless, we carried out one collaborative research project dealing with ghrelin and the ghrelin receptor. Ghrelin, a stomach-derived hormone implicated in numerous behaviors including feeding, reward, stress, and addictive behaviors, acts by binding to the growth hormone secretagogue receptor (GHSR). In this collaborative research project, we developed, verified, and carried out initial characterization of a novel GHSR knockout (KO) Wistar rat model created with CRISPR genome editing. Specifically, using CRISPR/Cas9, we developed a GHSR KO in a Wistar background. Loss of GHSR mRNA expression was histologically verified using RNAscope in wild-type (WT) and KO rats. We tested the effects of intraperitoneal acyl-ghrelin administration on food consumption and plasma growth hormone (GH) concentrations in WT and KO rats. We also analyzed locomotion, food consumption, and body fat composition in these animals. Body weight was monitored from early development to adulthood. The RNAscope analysis revealed an abundance of GHSR mRNA expression in the hypothalamus, midbrain, and hippocampus in WTs, and no observed probe binding in KOs. Ghrelin administration significantly increased plasma GH levels and food consumption in WT rats but not in KO rats. KO rats consumed significantly less food overall at basal conditions and weighed significantly less compared with WT rats throughout development. Compared with WT rats, KO rats presented significantly higher concentrations of brown adipose tissue. We verified GHSR deletion in our KO model using histological, physiological, neuroendocrinological, and behavioral measures. Our findings indicate that GHSR deletion in rats is not only associated with a lack of response to ghrelin, but also associated with decreases in daily food consumption and body growth, and increases in brown adipose tissue. This GHSR KO Wistar rat model provides a novel tool for studying the role of the ghrelin system in obesity and in a wide range of medical and neuropsychiatric disorders - including, potentially, drug addiction.
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