Introduction: As modern diseases such as depression and obesity become more prevalent, the need for investigations into the role of lifestyle factors in their development becomes more pressing. Studies have associated both stress and obesity with depression, however there are currently few studies that explore the role of combined subclinical stress and an obesogenic Western diet (WD) in the aetiology of depression. Subclinical stress refers to the stress as experienced by people in their everyday life due to work, family, or outside worldly events. Aims and hypothesis: The primary aim of this study was to assess whether subclinical stress and an obesogenic diet interact to promote metabolic disease and mood disorders such as MDD. A secondary aim of the study was to assess potential hormonal and neuronal changes induced by stress and the obesogenic WD and relate these to mood disorders. We hypothesised that chronic stress and a WD will act synergistically to promote metabolic disease and mood disorders. Methods: Sixty-four C57BL6/J mice randomly divided into 4 groups (n=16) Control (C), Western Diet (WD), control diet + restraint stress (C+RS), and WD+RS. WD macronutrient content was: 32% fat, 57% carbohydrate, 11% protein and 14% fat, 59% carbohydrate, 19% protein for the control diet. Two-hour restraint per day was used to induce restraint stress (RS) for the last two weeks of the 16-week feeding program used in the study. Body weight was assessed weekly and blood was collected after habituation and before sacrifice. Behavioural data was obtained using an open field test and sucrose preference test. Brain tissue and blood samples were collected after animal sacrifice. ELISAs were performed on regions of the brain thought to be impacted by depression and diabetes, specifically frontal cortex and hippocampus. ELISAs that were performed on the brain tissue included: norepinephrine, epinephrine, glutamate, dopamine, serotonin, −aminobutyric acid (GABA), cholesterol, and melatonin. Results: WD animals consumed more food in both absolute weight (P<0.0001) and in calorie content (P<0.0001), however the only significant difference in final body weight at sacrifice was between WD + stress and control diet + stress animals (P<0.05). No significant differences were found in post intervention (after 15 weeks feeding and 2 weeks restraint) glucose, triglycerides, or cholesterol. Fasting insulin (between stress groups: P<0.05, between non stressed groups: P<0.001) and HOMA-IR values were however significantly higher in WD animals (C+RS vs. WD+RS groups: P<0.01, and, C vs. WD groups P<0.001). Wall seeking behaviour in open field test (OFT) suggests heightened anxiety in animals exposed to stress while animals not exposed to stress displayed a reduction in locomotion post-intervention compared to pre-intervention OFT (P<0.01). WD animals also displayed features of anhedonia with the sucrose preference test (SPT) (P<0.001). The WD increased hippocampal leptin (P<0.05), and decreased hippocampal dopamine (P<0.05) and noradrenaline (P<0.01). Stress reduced frontal cortex BDNF (P<0.05) and increased frontal cortex glutamate (P<0.05). Combined stress and the western diet reduced levels of hippocampal BDNF (P<0.05) and tryptophan (P<0.05) and reduced frontal cortex levels of leptin (P<0.05). Conclusion: The WD successfully induced a prediabetic state due to a combination of hyperphagia and an increased caloric intake. Metabolic state was changed by Western diet to a pre-diabetic state, with increased insulin and HOMA-IR in the absence of elevated fasting glucose, triglycerides, or cholesterol. The WD also caused anhedonia which was associated with changes in hippocampal dopamine, leptin, and noradrenaline levels. Our data supports the additive effects of WD + subclinical stress on neural levels of BDNF, tryptophan, and leptin all of which are relevant to mood and metabolic disorders. A model of low-grade stress alone produced behavioural changes consistent with increased anxiety and modified BDNF and glutamate levels. Stress induced changes distinctly targeted the frontal cortex whereas all changes attributed to the WD occurred in the hippocampus.