Sexual dimorphism modulates metabolic and cognitive alterations under HFD nutrition and chronic stress exposure in mice. Correlation between spatial memory impairment and BDNF mRNA expression in hippocampus and spleen.

AIMS: The accumulated evidence suggests that lifestyle - specifically dietary habits and stress exposure - plays a detrimental role in health. The purpose of the present study was to analyze the interplay of stress, diet, and sex in metabolic and cognitive alterations. MAIN METHODS: For this purpose, one-month-old C57Bl/6J mice were fed with a standard diet or high-fat diet (HFD). After eight weeks, one subgroup of mice from each respective diet was exposed to 20 weeks of chronic mild stress (CMS), whilst the others were left undisturbed. KEY FINDINGS: After 28 weeks of HFD feeding, mice from both sexes were overweight, with an increase in caloric intake and abdominal and subcutaneous fat pads. Stress exposure induced a decrease in body weight, related to a decrease in caloric efficiency in both males and females. Results indicate that males are more susceptible than the females in modulating metabolic and cognitive functions under HFD and CMS. Although both sexes demonstrated HFD-induced weight gain, fat accumulation, insulin resistance, high cholesterol, only males exposed to CMS but not females have (i) impaired glucose tolerance with higher glucose level; (ii) significant prolonged latency in Barnes test, suggesting cognitive impairment; (iii) increased IFN-gamma expression in hippocampus, suggesting greater neuroinflammatory response; (iv) poorer cognitive performance related to a decrease in hippocampal and spleen BDNF mRNA expression. SIGNIFICANCE: The main finding in this study is the presence of a sexual dimorphism in modulating metabolic and cognitive functions under HFD and CMS, showing males are more susceptible than females. In addition, poorer cognitive performance was related to a decrease in hippocampal BDNF mRNA expression. Interestingly, these changes were observed in the spleen as well.

Influence of prenatal stress on metabolic abnormalities induced by postnatal intake of a high-fat diet in BALB/c mice.

Prenatal insults during fetal development result in increased likelihood of developing chronic disease. Obesity, the biggest risk factor for the development of metabolic disease, is affected by several genetic and environmental factors. High-fat diet (HFD) consumption is usually linked with the development of obesity. The main goal of this study was to analyze the impact of the exposure to a HFD in prenatally stressed animals. For this purpose, we subjected pregnant BALB/c mice to restraint stress for 2 h a day between gestational day (GD) 14 and GD 21. Prenatally stressed and control offspring of both sexes were postnatally exposed to a HFD for 24 weeks. We found that prenatal stress (PS) per se produced disturbances in males such as increased total blood cholesterol and triglycerides, with a decrease in mRNA expression of sirtuin-1. When these animals were fed a HFD, we observed a rise in glucose and insulin levels and an increase in visceral adipose tissue gene expression of leptin, resistin, and interleukin-1 beta. Although females proved to be more resilient to PS consequences, when they were fed a HFD, they showed significant metabolic impairment. In addition to the changes observed in males, females also presented an increase in body weight and adiposity and a rise in cholesterol levels.

Chronic Stress and Glucocorticoid Receptor Resistance in Asthma.

PURPOSE: Chronic and persistent exposure to negative stress can lead to adverse consequences on health. Particularly, psychosocial factors were found to increase the risk and outcome of respiratory diseases like asthma. Glucocorticoids (GCs) are the most efficient anti-inflammatory therapy for asthma. However, a significant proportion of patients don't respond adequately to GC administration. GC sensitivity is modulated by genetic and acquired disease-related factors. Additionally, it was proposed that endogenous corticosteroids may limit certain actions of synthetic GCs, contributing to insensitivity. Psychological and physiological stresses activate the hypothalamic-pituitary-adrenal axis, increasing cortisol levels. Here, we review the mechanism involved in altered GC sensitivity in asthmatic patients under stressful situations. Strategies for modulation GC sensitivity and improving GC therapy are discussed. METHODS: PubMed was searched for publications on psychological chronic stress and asthma, GC resistance in asthma, biological mechanisms for GC resistance, and drugs for steroid-resistant asthma, including highly potent GCs. FINDINGS: GC resistance in patients with severe disease remains a major clinical problem. In asthma, experimental and clinical evidence suggests that chronic stress induces inflammatory changes, contributing to a worse GC response. GC resistant patients can be treated with other broad-spectrum anti-inflammatory drugs, but these generally have major side effects. Different mechanisms of GC resistance have been described and might be useful for developing new therapeutic strategies against it. Novel drugs, such as highly potent GCs, phosphoinositide 3-kinase-delta inhibitors that reestablish histone deacetylase-2 function, decrease of GC receptor phosphorylation by p38 mitogen-activated protein kinase inhibitors, or phosphatase activators, are currently in clinical development and might be combined with GC therapy in the future. Furthermore, microRNAs (small noncoding RNA molecules) operate as posttranscriptional regulators, providing another level of control of GC receptor levels. Empirical results allow postulating that the detection and study of microRNAs might be a promising approach to better characterize and treat asthmatic patients. IMPLICATIONS: Many molecular and cellular pathobiological mechanisms are responsible of GC resistance. Therefore detecting specific biomarkers to help identify patients who would benefit from new therapies is crucial. Stress consitutes a negative aspect of current lifestyles that increase asthma morbidity and mortality. Adequate stress management could be an important and positive intervention.