Synergistic effects of low-level stress and a Western diet on metabolic homeostasis, mood, and myocardial ischemic tolerance

Abstract

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).

Stress‐induced body weight loss and improvements in cardiometabolic risk factors do not translate to improved myocardial ischemic tolerance in western diet‐fed mice

“…This finding is contrary to several studies (Du Toit et al, 2020; Fu et al, 2009; Pereira et al, 2016; Sousa Rodrigues et al, 2017), but corroborates several others (Bates et al, 2008; Bruder‐Nascimento et al, 2013; Finger et al, 2012; Garcia‐Diaz et al, 2007; Kai et al, 2000; Packard et al, 2014), and highlights the general lack of consistency in the effects of chronic stress on metabolic dysregulation. Habituation to the CRS and the loss of stress‐induced hyperglycemia may also explain the findings observed in the current study (Grissom & Bhatnagar, 2009; Rabasa et al, 2015).…”

“…Interestingly, CRS did not induce significant changes in LVDevP recovery on its own or in combination with WD feeding. This was unexpected since our previous work demonstrated a detrimental synergistic effect of these two interventions (Du Toit et al, 2020). Two considerations may explain this difference.…”

“…This raises questions about the relationship between metabolic disturbances and CVD outcomes under different physiological stress states (i.e., active vs. habituated). In our previous work, we noted that a short stressor (30 mins/day for 3 weeks) after a 10‐week WD diet feeding program synergistically disrupted metabolism culminating in worsened ischemic tolerance (Du Toit et al, 2020). The current study did not observe synergistic effects on metabolism, but still noted limited myocardial dysfunction in CRS‐exposed mice likely due to effects not related to metabolism.…”

“…Global normothermic ischemia was induced for 25 min, followed by 45 min of aerobic reperfusion. Time spent in ischemia was chosen based on previous work done by our lab and others (Du Toit et al, 2020; Wang et al, 2001). Peak systolic and EDP, heart rate, flow, and + and − dP / dt were continuously monitored at 1 kHz using an eight channel MacLab system (ADInstruments Pty Ltd.) connected to an Apple iMac computer.…”

“…This includes reports of both adverse and beneficial effects on cardiometabolic risk factors such as body weight, glycemic handling, and circulating insulin (Aslani et al, 2015; Finger et al, 2012; Fu et al, 2009; Kai et al, 2000; Sousa Rodrigues et al, 2017). Few studies have assessed interactions between DIO and psychological stress in governing cardiovascular phenotype and disease pathogenesis (Agrimi et al, 2019; Crestani, 2016; Du Toit et al, 2020). Thus, the relationship between metabolic homeostasis and cardiovascular outcomes within the context of chronic stress and DIO remains enigmatic.…”