Rats with a truncated ghrelin receptor (GHSR) do not respond to ghrelin, and show reduced intake of palatable, high-calorie food

Abstract

Ghrelin, a peptide hormone produced by the stomach, is the endogenous ligand for the Growth Hormone Secretagogue Receptor (GHSR). Ghrelin acts on the GHSR to increase food intake, appetitive behaviors, and adiposity. Recently, a rat model with a null mutation to the GHSR gene (FHH-GHSRm1/Mcwi) was generated and used in behavioral studies, but the basic metabolic phenotype of this strain as well as that of the background strain (Fawn Hooded Hypertensive, FHH) has not been characterized in detail. Here we compared male FHH-GHSRm1/Mcwi rats with their wild-type littermates (FHH-WT) in a number of metabolic parameters. In the 24h of recovery following an acute overnight fast, FHH-GHSRm1/Mcwi rats consumed less food than FHH-WT animals, and relative to their body weights, adult FHH-GHSRm1/Mcwi rats consumed fewer calories when placed on a high-fat diet. Despite this, FHH-GHSRm1/Mcwi rats did not show a difference in diet-induced obesity or weight gain. Fasted FHH-GHSRm1/Mcwi rats exhibited increased Agouti-Related Peptide (AgRP) and Neuropeptide Y (NPY) expression in the Arcuate Nucleus (ARC), indicative of altered central regulation of feeding and energy balance. FHH-GHSRm1/Mcwi rats exhibited lower levels of home cage locomotor behavior over the entire light/dark cycle, and reduced levels of food anticipatory activity when placed on a restricted feeding schedule. Finally, FHH-GHSRm1/Mcwi rats consumed less of a palatable dessert (cookie dough) given after the completion of the scheduled meal. Altogether, our data show that rats lacking a functional GHSR tend to eat less than their wild-type counterparts in the face of acute fasts, chronic high-fat diet exposure, and exposure to a palatable dessert, despite not showing differences in body weight and glucose homeostasis that are characteristic of GHSR null mice. These data indicate that many, but not all responses to GHSR ablation are conserved between rats and mice. The FHH-GHSRm1/Mcwi rat thus represents a novel and useful model for studying GHSR function in rats.