Glucocorticoid-induced insulin resistance is related to macrophage visceral adipose tissue infiltration.

Insulin resistance is frequently present in patients with glucocorticoid (GC) excess (Cushing's syndrome) or treated with high doses of GCs. Furthermore, others similarities between metabolic syndrome (visceral obesity, elevated blood glucose levels, dyslipidemia) and Cushing's syndrome suggest that GCs could play a role in obesity-linked complications. Here we reported that long-term corticosterone (CORT) exposure in mice induced weight gain, dyslipidemia as well as hyperglycaemia and systemic insulin resistance. CORT-treated mice exhibited an increased 11β-Hsd1 expression and corticosterone levels in fat depots but a specific upregulation of glucocorticoid receptor (Gr) and hexose-6-phosphate dehydrogenase only in gonadal adipose tissue, suggesting that GC could act differentially on various fat depots. Despite fat accumulation in all depots, an increased expression of adipogenic (Pparγ, C/ebpα) and lipogenic (Acc, Fas) key genes was restricted to gonadal adipose tissue. Hypertrophied adipocytes observed in both visceral and subcutaneous depots also resulted from reduced lipolytic activity due to CORT treatment. Surprisingly, GC treatment promoted macrophage infiltration (F4/80, Cd68) within all adipose tissues along with predominant M2-like macrophage phenotype, and can directly act on macrophages to induce this phenotype. Moreover, macrophage infiltration preceded mass gain and adipocyte hypertrophy. Of note, specific macrophage depletion in gonadal fat preferentially reduced the M2-like macrophage content, and partially restored insulin sensitivity in mice with GC-induced obesity and insulin resistance. These data provide evidence that GCs act on adipose tissue in a depot-dependent manner and that gonadal adipose macrophages are key effectors of GC-associated insulin resistance.
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