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

Compr Physiol. 2025 Oct;15(5):e70045. doi: 10.1002/cph4.70045.

ABSTRACT

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.

PMID:40916556 | DOI:10.1002/cph4.70045