To assess the interaction between stress and energy homeostasis, we immobilized male Sprague-Dawley rats prone to diet-induced obesity (DIO) or diet-resistance (DR) once for 20min and then fed them either low fat (4.5%) chow or a medium fat (31%) high energy (HE) diet for 9d. Stressed, chow-fed DIO rats gained less, while stressed DIO rats on HE diet gained more body weight, had higher feed efficiency and plasma leptin levels than unstressed controls. Neither stress nor diet affected DR body weight gain. While, stress-induced plasma corticosterone levels did not differ between phenotypes, DIO rats were initially more active in an open field and had higher hippocampal dentate gyrus and CA1 glucocorticoid receptor (GR) mRNA than DR rats, regardless of prior stress or diet. HE diet intake was associated with raised dentate gyrus and CA1 GR and amygdalar central nucleus (CeA) CRH mRNA expression, while stress was associated with reduced hypothalamic dorsomedial nucleus Ob-R mRNA and CeA CRH specifically in DIO rats fed HE diet. Thus, a single stress triggers a complex interaction among weight gain phenotype, diet and stress responsivity which determines the body weight and adiposity of a given individual.