Background Several fine-tuned and interconnected hypothalamic peptidergic systems orchestrate the regulation of energy homeostasis in the body. The orexigenic peptide ghrelin and the anorexigenic peptide leptin are among the most important, and both have been implicated in the development of eating disorders from obesity to anorexia nervosa.Objectives The goal of these studies was to examine the response of leptin-deficient ob/ob mice in ghrelin-receptor ligands in a food intake task.Methods Changes in cumulative food intake were measured after peripheral administration of ghrelin (1 and 2 nmol/10 g) and the ghrelin-receptor antagonist (D-Lys(3))-GHRP-6 (66.6 and 133.3 nmol/10 g) in obese and lean control mice during the light and dark cycle as well as in a state of food restriction. Hypothalamic ghrelin and ghrelin-receptor expression was measured in ob/ob and lean mice at two different timepoints.Results Ghrelin increased food intake in lean and obese mice in the light and dark cycle, whereas the ghrelin-receptor antagonist caused significantly stronger reduction in food intake in obese mice only in the dark cycle. After fasting, ob/ob mice displayed decreased light cycle sensitivity to the anorexigenic effects of the ghrelin-receptor antagonist. Hypothalamic expression levels of ghrelin were unaltered during the light cycle but decreased during the dark cycle in ob/ob mice; whereas, although unchanged in the light cycle, ghrelin-receptor expression was increased in the dark cycle in obese mice.Conclusion The functionality and sensitivity of the ghrelinergic system is dependent on the time of day and the satiety state in leptin-deficient ob/ob mice.