BACKGROUND: How low-level psychological stress and overnutrition interact in influencing cardiometabolic disease is unclear. Mechanistic overlaps suggest potential synergies, however findings are contradictory. We test whether low level stress and Western diet (WD) feeding synergistically influence homeostasis, mood and myocardial ischemic tolerance. METHODS: Male C57Bl6/J mice were fed a control or WD (32%/57%/11% calories from fat/carbohydrates/protein) for 12 wks, with subgroups restrained for 30 min/day over the final 3 wks. Metabolism, behavior, tolerance of perfused hearts to ischemia/reperfusion (I/R), and cardiac 'death proteins' were assessed. RESULTS: The WD resulted in insignificant trends to increased body weight (+5%), glucose (+40%), insulin (+40%), triglycerides (+15%) and cholesterol (+20%), and reduced leptin (-20%), while significantly reducing insulin sensitivity (100% rise in HOMA-IR, P<0.05). Restraint did not independently influence metabolism, while increasing HOMA-IR a further 50% (and resulting in significant elevations in insulin and glucose to 60-90% above control) in WD mice (P<0.05), despite blunting weight gain in control and WD mice. Anxiogenesis with restraint or WD was non-additive, whereas anhedonia (reduced sucrose consumption) only arose with their combination. Neuroinflammation markers (hippocampal TNF-a, Il-1b) were unchanged. Myocardial I/R tolerance was unaltered with stress or WD alone, while combination worsened dysfunction and oncosis (LDH efflux). Apoptosis (nucleosome accumulation) and death protein expression (BAK, BAX, BCL-2, RIP-1, TNF-α, cleaved caspase-3 and PARP) were unchanged. CONCLUSION: Mild, anxiogenic yet cardio-metabolically 'benign' stress interacts synergistically with a WD to disrupt homeostasis, promote anhedonia (independently of neuroinflammation), and impair myocardial ischemic tolerance (independently of apoptosis and death protein levels).