Abstract
Prolonged exposure to glucocorticoids (GCs) causes various metabolic derangements. These include obesity and insulin resistance, as inhibiting glucose utilization in adipose tissues is a major function of GCs. Although adipose tissue distribution and glucose homeostasis are sex-dependently regulated, it has not been evaluated whether GCs affect glucose metabolism and adipose tissue functions in a sex-dependent manner. In this study, high-dose corticosterone (rodent GC) treatment in C57BL/6J mice resulted in nonfasting hyperglycemia in male mice only, whereas both sexes displayed hyperinsulinemia with normal fasting glucose levels, indicative of insulin resistance. Metabolic testing using stable isotope-labeled glucose techniques revealed a sex-specific corticosterone-driven glucose intolerance. Corticosterone treatment increased adipose tissue mass in both sexes, which was reflected by elevated serum leptin levels. However, female mice showed more metabolically protective adaptations of adipose tissues than did male mice, demonstrated by higher serum total and high-molecular-weight adiponectin levels, more hyperplastic morphological changes, and a stronger increase in mRNA expression of adipogenic differentiation markers. Subsequently, in vitro studies in 3T3-L1 (white) and T37i (brown) adipocytes suggest that the increased leptin and adiponectin levels were mainly driven by the elevated insulin levels. In summary, this study demonstrates that GC-induced insulin resistance is more severe in male mice than in female mice, which can be partially explained by a sex-dependent adaptation of adipose tissues.
Highlights
Glucocorticoids (GCs) are steroid hormones produced by the adrenal gland
This study demonstrates that a high-dose corticosterone treatment causes insulin resistance in both sexes of mice, but with a more severe phenotype in male than in female mice
Our results show that corticosterone-treated female mice displayed a more protective feature in white adipose tissue (WAT) expansion and adipokine secretion than did corticosterone-treated male mice
Summary
Glucocorticoids (GCs) are steroid hormones produced by the adrenal gland. External stressors such as infection, trauma, food deprivation, and physical or psychological stress enhance the activity of the hypothalamic-pituitary-adrenal (HPA) axis and trigger. The fact that the concentrations of corticosteroid-binding globulin, the glycoprotein that binds 80% of circulating corticosterone, are higher in females than in males likely contributes to this sex difference [6, 8]. Sex steroid hormones are involved in the sex-dependent control of the HPA axis [6, 7]. Females have a relatively higher activity of the metabolically active brown adipose tissue (BAT) and have more brown-like adipocytes in their WAT depots [11, 12]. Glucose metabolism has been shown to differ between males and females, with female mice being more insulin sensitive and glucose tolerant than male mice [13]
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