While it is known that stress promotes obesity, the effects of stress within an obesogenic context are largely unclear and molecular targets at the interface remain elusive. The FK506 binding protein 51 (FKBP51, gene: Fkbp5) has been identified as a target gene implicated in the development of stress-related psychiatric disorders, and is a possible candidate involved in stress and metabolic regulation. The aims of the current study were to investigate the interaction between chronic stress and an obesogenic context and to additionally examine whether FKBP51 is involved in this interaction. For this purpose, male C57BL/6 mice were exposed to 8-weeks of a high fat diet before being challenged to chronic social defeat stress. Here we demonstrate that chronic stress induces hypophagia and weight loss, ultimately improving features arising from an obesogenic context, including glucose tolerance and levels of insulin and leptin. We show that Fkbp5 expression is responsive to diet and stress in the hypothalamus and hippocampus, respectively. Furthermore, under basal conditions, higher levels of hypothalamic FKBP51 expression were related to increased body weight gain. Our data indicate that FKBP51 may represent a novel target in metabolic regulation.