Glucocorticoid and circadian clock coregulation of insulin sensitivity and metabolism

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PROJECT SUMMARY/ABSTRACT Circadian rhythm plays a central role in metabolic homeostasis and nutrient utilization in nearly all organisms and virtually all tissues. Glucocorticoids are oscillatory regulators of metabolic function that act with cell and tissue-type specificity. Glucocorticoid steroids like prednisone are used to treat a wide range of inflammatory conditions, where their use is associated with prominent metabolic side effects. Chronic daily glucocorticoid intake promotes insulin resistance and obesity, and therefore novel approaches are needed to reverse these dysmetabolic effects. An important breakthrough in glucocorticoid-driven metabolic regulation stems from recently published discoveries that steroid dosing frequency, i.e. daily versus pulsatile weekly, promotes strikingly opposing effects on lean mass quality, exercise tolerance, and energy production. Contrary to daily dosing, weekly glucocorticoids exposure improves nutrient uptake and metabolism, boosting muscle growth and curtailing fat accrual. Specifically, I have uncovered that pulsatile glucocorticoids stimulate branched-chain amino acid oxidative metabolism and insulin sensitivity through a glucocorticoid receptor-responsive epigenomic program focusing on the transcriptional regulator Kruppel-like factor 15 (KLF15). Furthermore, pulsatile glucocorticoids also activate BMAL1 and its molecular cascades. Each of these components, the glucocorticoid receptor, KLF15 and BMAL1 are regulated by circadian oscillations in their metabolic effects. However, it is still unclear whether and how the circadian clock and glucocorticoid cascades interact to promote fuel utilization and favorable metabolic reprogramming, and whether environmental or genetic challenges to this interaction will affect metabolic physiology. To address this question, I propose to (i) dissect circadian regulation of glucocorticoid receptor activation and its effects on glucose and fatty acid utilization in metabolically active tissues like muscle, liver and fat, and (ii) investigate the epigenomic cross-regulation between BMAL1 and KLF15 in driving branched-chain amino acid metabolism and energy production. Experiments will follow a basic-to-translational path from mice models to human cells using a multidisciplinary approach encompassing epigenetic, molecular and metabolic studies. The overarching goal for this proposal is to provide new actionable knowledge of cross-regulation between glucocorticoids and circadian clock, with implications for the treatment of metabolic diseases like obesity and diabetes.