Glucocorticoid sensitization of microglia in a genetic mouse model of obesity and diabetes

Abstract

db/db mice are a model of obesity and diabetes due to their lack of functional leptin receptors, which leads to insulin resistance, elevated corticosterone levels, and persistent inflammation. Because stress-induced elevations in glucocorticoids sensitize microglia to immune challenges, we hypothesized that corticosteroids might act similarly in the diabetic brain. To test this hypothesis, db/db and wildtype mice were treated with the glucocorticoid synthesis inhibitor metyrapone every day for two weeks. This treatment revealed corticosterone-dependent increases in microglial number and accumulation of the pro-inflammatory cytokines interleukin 1beta and tumor necrosis factor alpha in the hippocampus of db/db mice. Analysis of microglial responses to lipopolysaccharide stimulation revealed that glucocorticoids lower the threshold for release of pro-inflammatory cytokines, underscoring the role of corticosteroids as a precipitating factor for neuroinflammation in obesity and diabetes.

Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease

“…Microglia was highly activated in APP/PS1xdb/db mouse brain, and to a lesser extent, a similar profile was observed when astrocytes were analyzed. Our data are in agreement with recent studies (Dey et al, 2014), supporting that obesity and T2D are accompanied by central neuroinflammation, that could ultimately interfere with learning and memory processes, and it remains plausible that inflammatory conditions may contribute to observed changes in A␤ species. It has been reported that microglia may try to clear A␤ (Morgan, 2006) in order to remove amyloid pathology.…”

Forced treadmill exercise can induce stress and increase neuronal damage in a mouse model of global cerebral ischemia

“…These results are in accordance with other studies where it has been shown that stress can evoke a pro-inflammatory response in the brain, with increased expression of NLRP3 inflammasome involved in the cleavage and secretion of pro-inflammatory IL-1β (Gadek-Michalska et al, 2013, Frank et al, 2014). Recently, it has been shown that a stress-induced increase in corticosterone levels lowers the threshold for microglia to release pro-inflammatory cytokines (Dey et al., 2014). Increased stress has even been suggested to exacerbate neuronal cell death by increasing neuroinflammation, which in turn is neurotoxic (de Pablos et al., 2014).…”

Blood–brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice

“…In a subset of mice, glycemic control was assessed with intraperitoneal glucose tolerance testing, as described. 29 All of the animal procedures used in these studies were approved by the Institutional Animal Care and Use Committee of Georgia Regents University and followed the NIH Guide for the Care and Use of Laboratory Animals, and the manuscript adheres to the ARRIVE (Animal Research: Reporting in Vivo Experiments) guidelines for reporting animal experiments.…”