Glucocorticoid signaling is required for fatty acid β-oxidation (FAO) via transcriptional regulation of carnitine palmitoyltransferase 1b (cpt1b) in zebrafish

Glucocorticoid (GC) signaling via glucocorticoid receptor (Gr) is crucial for vertebrate nutrient metabolism, but its regulatory role in lipid catabolism and the underlying the mechanism were still poorly understood. In this study, three hypocortisolism models of proopiomelanocortin (pomca)–/–, steroidogenic acute regulatory protein (star)–/–, cyp17a2–/– zebrafish, and one glucocorticoid resistance model of gr–/– zebrafish were used to investigate the role of GC signaling in lipid metabolism in vertebrates. Similar features of remodeled energy homeostasis, including accumulated fat deposition and enhanced glucose utilization, were observed in star–/–, cyp17a2–/–, and gr–/– zebrafish. Among the differentially expressed genes (DEGs) in liver, the carnitine palmitoyltransferase 1b (cpt1b) was identified as shared gene in star–/–, cyp17a2–/–, and gr–/– fish, compared to their respective control siblings. Administering hydrocortisone restored the decreased activity levels of fatty acid β-oxidation (FAO) activity and rescued the down-regulated hepatic and muscular expression of cpt1b in star–/–, cyp17a2–/– fish, but not in gr–/– fish. Furthermore, we demonstrated that GC could activate cpt1b expression by acting on its proximal promoter region via Gr. However, when the fold changes were calculated across the four deficient models (relative to their respective control siblings), pomca–/– fish exhibited the greatest relative increase in testosterone level, but the least decrease in relative cortisol level and cpt1b expression. Consequently, unlike the other three fish models with impaired GC signaling, no adiposity was observed in pomca–/–. Overall, our results suggest that GC signaling enhances FAO by promoting cpt1 expression, and the development of obesity due to impaired GC signaling depends on accompanying plasma steroid hormone profiles in fish.