Investigating the role of appetite-related hormones on energy balance and body composition when varying diets are consumed could provide insight into the etiology of obesity. Fifty-three adult male Sprague Dawley and 30 adult male Zucker Fatty rats were assigned randomly to one of five diets: Control, 75% control, American Heart Association (AHA), Atkins, or high fat (HF). Diets were fed for five weeks. Weekly plasma samples were collected and analyzed for ghrelin, leptin, insulin, and adiponectin. Terminal plasma samples were analyzed for ghrelin, leptin, insulin, glucagon, oxyntomodulin, adiponectin, and blood metabolites. Our results indicate that macronutrient composition of the diet influences appetite-related hormones differently in genetically divergent rats. For example, glucagon concentration was higher in obese rats fed the Atkins diet in comparison to obese rats fed the HF and 75% control diets (P<0.05) and tended to be higher in obese rats fed the Atkins diet in comparison with rats fed the AHA and control diets (0.06