K.J. Speaker

Interleukin-1 beta: a potential link between stress and the development of visceral obesity

BackgroundA disproportionate amount of body fat within the abdominal cavity, otherwise known as visceral obesity, best predicts the negative health outcomes associated with high levels body fat. Growing evidence suggests that repeated activation of the stress response can favor visceral fat deposition and that visceral obesity may induce low-grade, systemic inflammation which is etiologically linked to the pathogenesis of obesity related diseases such as cardiovascular disease and type 2 diabetes. While the obesity epidemic has fueled considerable interest in these obesity-related inflammatory diseases, surprisingly little research is currently focused on understanding the functions of inflammatory proteins in healthy, non-obese white adipose tissue (WAT) and their possible role in modulating stress-induced shifts in body fat distribution.HypothesisThe current review presents evidence in support the novel hypothesis that stress-evoked interleukin-1 beta (IL-1β) signaling within subcutaneous adipose tissue, when repeatedly induced, contributes toward the development of visceral obesity. It is suggested that because acute stressor exposure differentially increases IL-1β levels within subcutaneous adipose relative to visceral adipose tissue in otherwise healthy, non-obese rats, repeated induction of this response may impair the ability of subcutaneous adipose tissue to uptake energy substrates, synthesize and retain triglycerides, and/or adapt to positive energy balance via hyperplasia. Consequently, circulating energy substrates may be disproportionately shunted to visceral adipose tissue for storage, thus driving the development of visceral obesity.ConclusionsThis review establishes the following key points: 1) body fat distribution outweighs the importance of total body fat when predicting obesity-related disease risk; 2) repeated exposure to stress can drive the development of visceral obesity independent of changes in body weight; 3) because of the heterogeneity of WAT composition and function, an accurate understanding of WAT responses requires sampling multiple WAT depots; 4) acute, non-pathogenic stressor exposure increases WAT IL-1β concentrations in a depot specific manner suggesting an adaptive, metabolic role for this cytokine; however, when repeated, stress-induced IL-1β in non-visceral WAT may result in functional impairments that drive the development of stress-induced visceral obesity.

Adrenergic and glucocorticoid modulation of the sterile inflammatory response

Exposure to an intense, acute stressor, in the absence of a pathogen, alters immune function. Exposure to a single bout of inescapable tail shock increases plasma and tissue concentrations of cytokines, chemokines, and the danger associated molecular pattern (DAMP) Hsp72. Although previous studies have demonstrated that adrenergic receptor (ADR) and glucocorticoid receptor (GCR)-mediated pathways alter pathogen or microbial associated molecular pattern (MAMP)-evoked levels of cytokines, chemokines, and Hsp72, far fewer studies have tested the role of these receptors across multiple inflammatory proteins or tissues to elucidate the differences in magnitude of stress-evoked sterile inflammatory responses. The goals of the current study were to (1) compare the sterile inflammatory response in the circulation, liver, spleen, and subcutaneous (SQ) adipose tissue by measuring cytokine, chemokine, and DAMP (Hsp72) responses; and (2) to test the role of alpha-1 (α1), beta-1 (β1), beta-2 (β2), and beta-3 (β3) ADRs, as well as GCRs in signaling the sterile inflammatory response. The data presented indicate plasma and SQ adipose are significantly more stress responsive than the liver and spleen. Further, administration of ADR and GCR-specific antagonists revealed both similarities and differences in the signaling mechanisms of the sterile inflammatory response in the tissues studied. Finally, given the selective increase in the chemokine monocyte chemotactic protein-1 (MCP-1) in SQ tissue, it may be that SQ adipose is an important site of leukocyte migration, possibly in preparation for infection as a consequence of wounding. The current study helps further our understanding of the tissue-specific differences of the stress-induced sterile inflammatory response.

A Single Bout of Fasting (24 h) Reduces Basal Cytokine Expression and Minimally Impacts the Sterile Inflammatory Response in the White Adipose Tissue of Normal Weight F344 Rats

Sterile inflammation occurs when inflammatory proteins are increased in blood and tissues by nonpathogenic states and is a double-edged sword depending on its cause (stress, injury, or disease), duration (transient versus chronic), and inflammatory milieu. Short-term fasting can exert a host of health benefits through unknown mechanisms. The following experiment tested if a 24 h fast would modulate basal and stress-evoked sterile inflammation in plasma and adipose. Adult male F344 rats were either randomized to ad libitum access to food or fasted for 24 h prior to 0 (control), 10, or 100, 1.5 mA-5 s intermittent, inescapable tail shocks (IS). Glucose, nonesterified free fatty acids (NEFAs), insulin, leptin, and corticosterone were measured in plasma and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-10 in plasma, and subcutaneous, intraperitoneal, and visceral compartments of white adipose tissue (WAT). In control rats, a 24 h fast reduced all measured basal cytokines in plasma and visceral WAT, IL-1β and IL-6 in subcutaneous WAT, and IL-6 in intraperitoneal WAT. In stressed rats (IS), fasting reduced visceral WAT TNF-α, subcutaneous WAT IL-1β, and plasma insulin and leptin. Short-term fasting may thus prove to be a useful dietary strategy for reducing peripheral inflammatory states associated with visceral obesity and chronic stress.

Psychological stress affects LPS-induced vascular inflammatory proteins

275 Strenuous physical stress increases risk of respiratory tract infection (RTI) M. Pannacci, V. Lucini, A. Caronno, S. Dugnani, F. Scaglione University of Milan, Dept.Pharmacology, Milan 20159, Italy Moderate exercise activates innate immunological response while strenuous exercise seems to impair it. However molecular mechanisms are not clearly described. RTI in athletes is greater than sedentary controls. In alveolar epithelial cells, dual-oxidase enzymes (DUOX1 and DUOX2) are involved in bacterial killing through production of ROS. The purpose of this work was to evaluate susceptibility to RTI in a model of experimental infection in mice subjected to physical stress. Mice Balb/c were subjected to swimming for 1 h/day for 4 weeks; after moderate and chronic exercise, animals were infected with 1 10 CFU of S. pneumoniae. Infection was evaluated by bacterial count and histological analysis; changes in gene expression of DUOX1–DUOX2 were evaluated by Real Time PCR on RNA extracted from tissue. Controls and chronic stressed mice resulted infected. Pneumonia was markedly extended in stressed group compared to controls. Bacterial size was significantly higher (p < 0.001) in chronic stressed animals vs controls (4 10 ± 2.5 CFU/lung vs 3 10 ± 2 CFU/lung). Only 30% of mice subjected to moderate exercise resulted infected (2 10 ± 1.4 CFU/lung). DUOX1–DUOX2 expression increased significantly in control infected mice (p < 0.05) and in those subjected to moderate exercise (p < 0.001), but unchanged in mice undergo to chronic exercise. Data obtained confirmed that prolonged exercise increases susceptibility to RTI; moreover we showed for the first time that RTI is linked to changes in DUOX1–DUOX2 expression. doi:10.1016/j.bbi.2010.07.063

Acute stressor exposure suppresses the innate response to bacteremia

261 Behavioral stress reduces therapeutic sensitivity of prostate cancer S. Hassan, V. Baurin, Y. Karpova, D. Yancey, D. Perry, M. Cline, G. Kulik Wake Forest University, Winston-Salem, NC, USA Recently we have demonstrated that epinephrine at concentrations observed during behavioral stress induces PKA dependent phosphorylation of the pro-apoptotic protein BAD and prevent apoptosis in prostate cancer cells. Yet, it was not clear whether behavioral stress could activate anti-apoptotic signaling in prostate tumors in vivo and whether epinephrine induced BAD phosphorylation is the dominant mechanism that mediates anti-apoptotic effect of stress. We report that subjecting mice to behavioral stress by immobilization and exposure to fox urine scent resulted in increase of serum epinephrine level leading to activation of the b2-adrenergic receptor (ADRB2) and protein kinase A (PKA) pathway in prostate tumors. This ADRB2/PKA activation is necessary for in vivo BAD phosphorylation and protection of prostate tumors from apoptosis induced by PI3K inhibitors. Noninvasive monitoring of prostate cancer xenografts by luminescent imaging has shown that PI3K inhibitors substantially reduced luminescence of xenograft tumors. Anti-tumor effects of PI3K inhibitors were significantly decreased when mice were subjected to behavioral stress. Prostate cancer patients are characterized by increased levels of stress and anxiety. Analysis of plasma epinephrine levels in prostate cancer patients have shown that in 15% of patients epinephrine levels exceed 1 nM, which is sufficient to activate anti-apoptotic signaling in mouse models. Thus, elevated epinephrine levels could contribute to therapy resistance of prostate cancer. doi:10.1016/j.bbi.2010.07.053

118. Effects of voluntary exercise on acute stress responses in white adipose tissue

IL-12 is the major Th1 differentiation factor, and a potent proinflammatory/pro-CMI-Th1 cytokine. Stress is believed to perturb Th1 status, but the evidence is mostly based on in vitro induced production (IVIP) studies that are affected by sample cellular composition, and employ adjuvant stimulation in an artificial milieu. Here we studied serum IL-12 levels in rats following different stress paradigms, in vivo stress hormone administration, and employment of specific blockers. Simultaneously, IL-12 IVIP was studied. Results: Corticosterone (1 mg/kg/h), epinephrine (0.02 mg/kg/h), and prostaglandin (0.03 mg/kg/h) administered in a slow-release preparation and at physiologically relevant doses, each reduced baseline IL-12 serum levels ( 300 pg/ml) by up to 3-fold at 5 and 10 h after administration. No circadian IL-12 rhythm was evident. Social confrontation (12 h), 2 cm water stress (10 h), and surgery (laparotomy), reduced baseline levels by approximately 2-fold; reduction following surgery was noticeable at 2 h, significant at 6 h, maximized at 12–24 h, and began dissipating at 48 h. IVIP mimicked only a small portion of these effects. We are currently attempting to abolish stressand surgery-induced serum IL-12 reduction by simultaneously employing blockers for corticosterone, prostaglandin, and beta-adrenoceptors, as the solitary use of any blocker was ineffective. Conclusions: The stressand surgery-induced decrease in serum IL-12 levels is a robust and multi-factorial phenomenon in rats, suggesting its biological significance. The ex-vivo induced production approach seems to reflect different aspects of the cytokine system.