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

• Pharmacological inhibition of corticosterone attenuates microgliosis in db/db mice.
• Metyrapone blocks hippocampal cytokine accumulation in db/db mice.
• Corticosterone sensitizes microglia to ex vivo immune stimulation in db/db mice.

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 2 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.

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