No abstract

Restraint stress stimulates sympathetic nerve activity and can affect adiposity and metabolism. However, the effects of restraint stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS) have remained unclear. We investigated the effects of chronic restraint stress and β-adrenergic receptor (β-AR) blockade on cardiac and adipose tissue pathology and metabolic disorders in a rat model of MetS. DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats. Rats were exposed to restraint stress (restraint cage, 2 h/day) for 4 wk from 9 wk of age with or without daily subcutaneous administration of the β-AR blocker propranolol (2 mg/kg). Age-matched homozygous lean littermates of DS/obese rats (DahlS.Z-Lepr(+)/Lepr(+) rats) served as control animals. Chronic restraint stress exacerbated hypertension as well as left ventricular hypertrophy, fibrosis, diastolic dysfunction, and oxidative stress in a manner sensitive to propranolol treatment. Restraint stress attenuated body weight gain in DS/obese rats, and this effect tended to be reversed by propranolol (P = 0.0682). Restraint stress or propranolol did not affect visceral or subcutaneous fat mass. However, restraint stress potentiated cardiac and visceral adipose tissue inflammation in DS/obese rats, and these effects were ameliorated by propranolol. Restraint stress also exacerbated glucose intolerance, insulin resistance, and abnormal lipid metabolism in a manner sensitive to propranolol. In addition, restraint stress increased urinary norepinephrine excretion, and propranolol attenuated this effect. Our results thus implicate β-ARs in the exacerbation of cardiac and adipose tissue pathology and abnormal glucose and lipid metabolism induced by restraint stress in this model of MetS.

Introduction: Chronic stress, when combined with hyperphagia, can affect adiposity and metabolism. However, few studies have reported the effects of cold stress on cardiovascular and metabolic disorders in metabolic syndrome (MetS). We investigated the effects of chronic cold stress and glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology and gene expression and on glucose and lipid metabolism in a rat model of MetS. Methods and Results: We used DahlS.Z-Leprfa/Leprfa (DS/obese) rats which are derived from a cross between Dahl salt-sensitive and Zucker rats and represent a new animal model of MetS. DS/obese rats were exposed to cold stress (ice-cold water, 1 cm depth, 2 h/day) for 4 weeks beginning at 9 weeks of age with or without the GR antagonist RU486 (2 mg/kg/day, sc). Age-matched homozygous lean (DahlS.Z-Lepr+/Lepr+, or DS/lean) littermates of DS/obese rats served as controls. Chronic cold stress exacerbated hypertension as well as left ventricular (LV) hypertrophy, fibrosis and diastolic dysfunction, in a manner sensitive to RU486. Cold stress and RU486 did not affect body weight or visceral and subcutaneous fat mass. In contrast, cold stress further increased superoxide production and NADPH oxidase activity in the heart as well as macrophage infiltration and the expression of proinflammatory genes in LV and visceral fat tissue. RU486 treatment inhibited these changes in gene expression, as well as cardiac oxidative stress and inflammation and adipose tissue inflammation. Cold stress further up-regulated cardiac renin-angiotensin-aldosterone system gene expression as well as the expression of GR and 11β-hydroxysteroid dehydrogenase type 1 genes in LV and visceral adipose tissue, and all of these effects were attenuated by RU486. In addition, RU486 ameliorated the stress-induced deterioration of dyslipidemia (elevations in low-density lipoprotein cholesterol, triglycerides, and free fatty acid) as well as that of glucose intolerance and insulin resistance. Conclusions: The present results indicate that GRs may be involved in cold stress-induced exacerbation of cardiac and adipose tissue pathology as well as that of glucose and lipid metabolism in a rat model of MetS.