Individual and Comorbid Influences of Chronic Stress and a Western Diet on Allostatic Loads and Cardiac Resilience, Adaptation and Proteome Profiles in Male Mice

Mechanisms underlying cardiovascular, affective, and metabolic (CAM) multimorbidity are incompletely defined. We assessed how two risk factors—chronic stress (CS) and a Western diet (WD)—interact to influence cardiovascular function, resilience, adaptability, and allostatic load (AL); explore pathway involvement; and examine relationships with behavioral, metabolic, and systemic AL. Male C57Bl/6 mice (8 weeks old, n = 64) consumed a control (CD) or WD (12%–65%–23% or 32%–57%–11% calories from fat‐carbohydrate‐protein) for 17 weeks, with half subjected to 2 h daily restraint stress over the final 2 weeks (CD + CS and WD + CS). The WD induced a pre‐diabetic state (increased weight, hyperinsulinemia, insulin‐resistance, and hyperleptinemia) and anhedonia, while CS reduced body weight and leptin levels and was anxiogenic. The cardiovascular system was particularly stress sensitive: the WD worsened resilience (vulnerability to ischemia–reperfusion; I‐R), while CS increased cardiac automaticity, reduced contractility and relaxation, worsened postischemic inflammation (TNF‐α) and inhibited adaptive resilience (efficacy of ischemic preconditioning; PC). Proteomics identified mitochondrial function, innate immunity, and xenobiotic metabolism as prominently modified processes. Regarding allostatic loading: comorbid CS and WD feeding were necessary to increase cardiovascular AL and additively increased behavioral AL; the WD (not CS) increased metabolic, neuroendocrine‐immune, and systemic AL. Summarizing: (i) distinct changes arise with CS (disrupted cardiac function, inflammation, adaptation; weight loss; anxiogenesis) versus a WD (reduced cardiac resilience; prediabetes; anhedonia); (ii) comorbid WD and CS additively worsen cardiovascular and behavioral AL; and (iii) mitochondrial and innate defense processes may underlie cardiac effects of diet and stress. Data support positive diet‐stress interactions that particularly increase cardiovascular and affective vulnerability.