OBJECTIVE Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disorders such as osteoporosis in adults and growth retardation in children and adolescents. Prevention and care of the GC-induced adverse effects remain challenging. We have previously demonstrated the efficacy of a treatment with a non-peptidic agonist of adiponectin receptors, AdipoRon, to reverse behaviour disorders and fat mass gain induced by long-term GC treatment. In this work, we have established a relevant model of GC-induced growth and metabolic disorders and determined that AdipoRon is a potential therapeutic tool to reverse these metabolic disturbances. METHODS 5-Week-old mice were treated continuously with or without corticosterone (35 mg/L) in drinking water for seven consecutive weeks. Taking advantage of this mouse model displaying various growth and metabolic disorders, we assayed whether AdipoRon (daily intraperitoneal injection of 1 mg/kg/day for the last 20 days) might prevent the GC-induced adverse effects. The control group was treated with vehicle only. Nutritional behaviors and metabolic parameters were followed-up throughout the treatment. Serum insulin and leptin levels were measured by ELISA. Computed tomography and histological analysis of adipose tissue were assessed at the end of the experimental procedure. RESULTS We found that GC treatment in young mice resulted in continuously increased body weight gain associated with a food intake increase. Compared to vehicle-, GC-treated mice displayed early major hyperleptinemia (up to 6-fold more) and hyperinsulinemia (up to 20-fold more) maintained throughout the treatment. At the end of the experimental procedure, GC-treated mice displayed bone growth retardation (e.g. femur length 15.1 versus 14.0 mm, P < 0.01), higher abdominal adipose tissue volume (4.1 versus 2.3, P < 0.01) and altered glucose metabolism compared to control mice. Interestingly, AdipoRon prevented GC-induced effects on energy metabolism such as abdominal adiposity, insulinemia and leptinemia. However, AdipoRon failed to counteract bone growth retardation. CONCLUSION We characterized the very early pathological steps induced by long-term GC in young mice in a relevant model, including growth retardation, fat mass gain and glucose homeostasis dysregulation. The adiponectin system stimulation enabled normalization of the adipose tissue and metabolic features of GC-treated mice. Adiponectin receptor agonists such as AdipoRon might constitute a novel way to counteract some GC-induced adverse effects.

中文翻译：

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脂联素受体激动剂AdipoRon可使葡萄糖代谢正常化，并防止肥胖，但不能预防糖皮质激素在幼年小鼠中引起的生长迟缓。

目的糖皮质激素（GCs）是高效的抗炎和免疫抑制药物。但是，长时间的GC治疗可能会导致许多不良反应，导致糖尿病和肥胖症，以及骨骼疾病，例如成人骨质疏松症和儿童和青少年的发育迟缓。预防和护理GC引起的不良反应仍然具有挑战性。先前我们已经证明了用脂联素受体的非肽激动剂AdipoRon治疗可以逆转长期GC治疗引起的行为障碍和脂肪增加。在这项工作中，我们已经建立了由GC引起的生长和代谢紊乱的相关模型，并确定AdipoRon是逆转这些代谢紊乱的潜在治疗工具。方法连续7周对5周龄小鼠在饮用水中连续或不连续35 mg / L皮质酮治疗。利用显示各种生长和代谢异常的这种小鼠模型，我们分析了AdipoRon（最近20天每天腹膜内注射1 mg / kg /天）是否可以预防GC诱导的不良反应。对照组仅用媒介物治疗。在整个治疗过程中对营养行为和代谢参数进行跟踪。通过ELISA测量血清胰岛素和瘦素水平。在实验过程结束时评估了计算机的层析成像和脂肪组织的组织学分析。结果我们发现，在幼鼠中进行GC治疗后，体重增加与食物摄入量增加有关而持续增加。与车辆相比，用GC治疗的小鼠在整个治疗过程中均表现出早期的主要高瘦素血症（最多增加了6倍）和高胰岛素血症（最多增加了20倍）。在实验过程结束时，GC处理的小鼠显示出骨骼生长迟缓（例如股骨长15.1对14.0 mm，P <0.01），较高的腹部脂肪组织体积（4.1对2.3，P <0.01）和葡萄糖代谢发生改变（与对照小鼠。有趣的是，AdipoRon预防了GC诱导的对能量代谢的影响，例如腹部肥胖，胰岛素血症和瘦素血症。但是，AdipoRon无法抵消骨骼生长迟缓。结论在相关模型中，我们表征了长期GC诱导的年轻小鼠早期病理步骤，包括生长迟缓，脂肪质量增加和葡萄糖稳态失调。脂联素系统刺激使脂肪组织和GC处理小鼠的代谢特征正常化。脂联素受体激动剂（例如AdipoRon）可能构成抵消某些GC诱导的不良反应的新颖方法。