Adipose and Muscle Tissue in Glucocorticoid-Induced Metabolic Disease

Abstract

Introduction: Glucocorticoids are steroid hormones induced by stress that are necessaryfor proper glucose homeostasis and tissue development. Glucocorticoids also have potent immunosuppressant properties and are commonly used to treat a variety of inflammatory conditions such as asthma, cancer and autoimmune disease in children and adults. Chronic elevations due to excess stress or chronic glucocorticoid treatment can lead to metabolic disease. Though glucocorticoid-induced metabolic disturbances such as insulin resistance, non-alcoholic fatty liver disease (NAFLD) and muscle wasting are well known, the impact of pre-existing obesity on metabolic syndrome and the specific transcriptional changes leading to these outcomes remain undefined. Additionally, the effects of childhood glucocorticoid exposure on adult metabolic health is largely unknown. The aim of this dissertation is to identify the underlying physiological and mechanistic processes that lead to poor metabolic health following chronically elevated glucocorticoids, and how obesity status affects glucocorticoid-induced metabolic disease, focusing on effects in adipose and muscle. Methods: To determine the impact of obesity on glucocorticoid associated metabolic disease, clinical measures and adipose tissue transcriptional changes were studied in lean and obese patients with Cushing’s disease. To extend these findings, lean and obese mice were treated with dexamethasone and a variety of physiological and biochemical outcomes related to metabolic syndrome were assessed. To understand the contribution of the adipocyte glucocorticoid receptor (GR) in dexamethasone-induced metabolic disease, metabolic disease outcomes were measured in lean and obese GR knockout mice. Dexamethasone regulation of adipogenic genes was also assessed in adipocytes in order to determine potential GR targets during early adipogenesis, a process negatively associated with insulin resistance. Lastly, juvenile dexamethasone exposure studies were conducted in mice to determine how this affects body composition and glucose homeostasis in adulthood. Results: Obesity resulted in synergistic elevations of glucocorticoid-induced lipolysis, insulin resistance, NAFLD and muscle atrophy. Ablation of the adipocyte GR attenuated these effects, with the exception of muscle loss. In regards to dexamethasone-induced adipogenesis, Klf5 was induced early and in the absence of other stimuli, suggesting it may be a promising target for future study. Evidence of reduced glucose tolerance was observed in adult male and female mice following short-term juvenile exposure to dexamethasone. Reduced lean and fat mass was noted in dexamethasone-treated adult male mice, suggesting that male mice are more susceptible to adverse outcomes during this window of exposure. Conclusion: Diet-induced obesity amplifies the adverse metabolic outcomes of glucocorticoids, such as insulin resistance and NAFLD, in humans and mice, as well as exacerbates muscle wasting in mice. These data implicate adipose as a key tissue in glucocorticoid-induced systemic insulin resistance and NAFLD, though it is unclear how obesity is leading to greater dexamethasone-induced muscle wasting, and support that lipolysis is the most likely mediator linking adipocyte glucocorticoid action to metabolic disease. Additionally, short-term juvenile dexamethasone exposure was shown to disrupt normal glucose regulation in adult mice and had negative impacts on lean mass in male mice. Further studies focus on the specific mechanisms linking glucocorticoid signaling in adipocytes to insulin resistance, NAFLD and muscle health, as well as how obesity exacerbates these outcomes. Future research is also warranted to fully elucidate the impact of childhood glucocorticoid exposure on metabolic health in adulthood. The findings presented here contribute to the greater body of research and could potentially be used to influence treatment strategies for those with elevated glucocorticoids.