Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil.
PLoS One. 2013 Aug 14;8(8):e71944. doi: 10.1371/journal.pone.0071944. eCollection 2013.
This study tested whether chronic systemic administration of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) could attenuate hyperphagia, reduce lean and fat mass losses, and improve whole-body energy homeostasis in insulin-deficient rats. Male Wistar rats were first rendered diabetic through streptozotocin (STZ) administration and then intraperitoneally injected with AICAR for 7 consecutive days. Food and water intake, ambulatory activity, and energy expenditure were assessed at the end of the AICAR-treatment period. Blood was collected for circulating leptin measurement and the hypothalami were extracted for the determination of suppressor of cytokine signaling 3 (SOCS3) content, as well as the content and phosphorylation of AMP-kinase (AMPK), acetyl-CoA carboxylase (ACC), and the signal transducer and activator of transcription 3 (STAT3). Rats were thoroughly dissected for adiposity and lean body mass (LBM) determinations. In non-diabetic rats, despite reducing adiposity, AICAR increased (∼1.7-fold) circulating leptin and reduced hypothalamic SOCS3 content and food intake by 67% and 25%, respectively. The anorexic effect of AICAR was lost in diabetic rats, even though hypothalamic AMPK and ACC phosphorylation markedly decreased in these animals. Importantly, hypothalamic SOCS3 and STAT3 levels remained elevated and reduced, respectively, after treatment of insulin-deficient rats with AICAR. Diabetic rats were lethargic and displayed marked losses of fat and LBM. AICAR treatment increased ambulatory activity and whole-body energy expenditure while also attenuating diabetes-induced fat and LBM losses. In conclusion, AICAR did not reverse hyperphagia, but it promoted anti-catabolic effects on skeletal muscle and fat, enhanced spontaneous physical activity, and improved the ability of rats to cope with the diabetes-induced dysfunctional alterations in glucose metabolism and whole-body energy homeostasis.
本研究旨在探讨慢性系统性给予 5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖核苷酸（AICAR）是否可以减轻胰岛素缺乏型大鼠的多食症、减少瘦体重和脂肪量的损失，并改善全身能量稳态。雄性 Wistar 大鼠首先通过链脲佐菌素（STZ）给药使其发生糖尿病，然后连续 7 天腹腔内注射 AICAR。在 AICAR 治疗期末，评估食物和水的摄入、活动能力和能量消耗。收集血液以测量循环瘦素，提取下丘脑以测定抑制细胞因子信号转导 3（SOCS3）含量，以及 AMP-激酶（AMPK）、乙酰辅酶 A 羧化酶（ACC）和信号转导和转录激活因子 3（STAT3）的含量和磷酸化。对大鼠进行彻底解剖以确定体脂和瘦体重（LBM）。在非糖尿病大鼠中，尽管 AICAR减少了体脂，但增加了（约 1.7 倍）循环瘦素，并使下丘脑 SOCS3 含量和食物摄入量分别减少了 67%和 25%。然而，在糖尿病大鼠中，AICAR 的厌食作用消失了，尽管这些动物的下丘脑 AMPK 和 ACC 磷酸化明显降低。重要的是，在胰岛素缺乏型大鼠用 AICAR 治疗后，下丘脑 SOCS3 和 STAT3 水平仍然升高和降低。糖尿病大鼠表现出嗜睡和明显的脂肪和 LBM 损失。AICAR 治疗增加了活动能力和全身能量消耗，同时减轻了糖尿病引起的脂肪和 LBM 损失。总之，AICAR 没有逆转多食症，但它促进了对骨骼肌和脂肪的抗分解代谢作用，增强了自发的体力活动，并改善了大鼠应对糖尿病引起的葡萄糖代谢和全身能量稳态功能障碍改变的能力。
