Selenium at the intersection of glucocorticoids and metabolic disorder

University Of Hawaii At Manoa, Honolulu HI

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Abstract

Glucocorticoids (GCs) are commonly prescribed in humans for their anti-inflammatory and immunosuppressive properties, but long-term consumption can cause metabolic side-effects, such as overeating, excess weight gain, and glucose imbalance. Past work suggests an interaction between GCs and the essential trace element selenium (Se). Work in mouse models has shown that Se-based therapy can alleviate the neurological symptoms of stress and exogenous corticosterone (CORT) administration. Conversely, CORT has been shown to affect selenoprotein expression in several different tissues and cell types. To date, there has not been a comprehensive study on the effects of CORT on Se homeostasis throughout the body. Preliminary data has shown altered selenoprotein levels in tissues from mice administered CORT for 4-6 weeks, including elevated Selenoprotein P (SELENOP) in blood and liver. SELENOP delivers dietary Se throughout the body, and has also been proposed to play a role in the development of metabolic disorders. This project will determine the impact of long-term CORT consumption on Se homeostasis throughout the body, as well as the role of SELENOP in CORT-induced metabolic disturbances. The central hypothesis is that CORT-induced dys-homeostasis of Se and selenoprotein levels lead to metabolic impairments. This hypothesis will be investigated through the following specific aims: Specific Aim 1: Determine if CORT disrupts the distribution of Se throughout the body. Hypothesis: CORT will increase Se content in certain tissues that rely on SELENOP while decreasing Se in other tissues. Specific Aim 2: Determine if SELENOP mediates CORT-induced metabolic dysfunction. Hypothesis: Elevated SELENOP promotes weight gain in mice through actions in the hypothalamus and brown adipose tissue. Mice will be administered CORT via drinking water and will undergo comprehensive metabolic phenotyping, including the use of metabolic cages and implantable temperature probes. Tissues will be analyzed for Se content using total reflection x-ray fluorescence (TXRF) spectrometry. Additionally, markers of cellular stress and dysfunction will be assayed in brown adipose tissue, pancreas and hypothalamus. We predict that our results will provide important insights on the interactions between GCs and Se, and their impact on energy homeostasis.