Department of Pharmacology and Neurosciences Institute, School of Medicine, University of Granada, Granada, Spain.
J Pineal Res. 2014 Aug;57(1):103-9. doi: 10.1111/jpi.12147. Epub 2014 Jul 10.
Mitochondrial dysfunction in adipose tissue may contribute to obesity-related metabolic derangements such as type 2 diabetes mellitus (T2DM). Because mitochondria are a target for melatonin action, the goal of this study was to investigate the effects of melatonin on mitochondrial function in white (WAT) and beige inguinal adipose tissue of Zücker diabetic fatty (ZDF) rats, a model of obesity-related T2DM. In this experimental model, melatonin reduces obesity and improves the metabolic profile. At 6 wk of age, ZDF rats and lean littermates (ZL) were subdivided into two groups, each composed of four rats: control (C-ZDF and C-ZL) and treated with oral melatonin in the drinking water (10 mg/kg/day) for 6 wk (M-ZDF and M-ZL). After the treatment period, animals were sacrificed, tissues dissected, and mitochondrial function assessed in isolated organelles. Melatonin increased the respiratory control ratio (RCR) in mitochondria from white fat of both lean (by 26.5%, P < 0.01) and obese (by 34.5%, P < 0.01) rats mainly through a reduction of proton leaking component of respiration (state 4) (28% decrease in ZL, P < 0.01 and 35% in ZDF, P < 0.01). However, melatonin treatment lowered the RCR in beige mitochondria of both lean (by 7%, P < 0.05) and obese (by 13%, P < 0.05) rats by maintaining high rates of uncoupled respiration. Melatonin also lowered mitochondrial oxidative status by reducing nitrite levels and by increasing superoxide dismutase activity. Moreover, melatonin treatment also caused a profound inhibition of Ca-induced opening of mPTP in isolated mitochondria from both types of fat, white and beige, in both lean and obese rats. These results demonstrate that chronic oral melatonin improves mitochondrial respiration and reduces the oxidative status and susceptibility to apoptosis in white and beige adipocytes. These melatonin effects help to prevent mitochondrial dysfunction and thereby to improve obesity-related metabolic disorders such as diabetes and dyslipidemia of ZDF rats.
脂肪组织中线粒体功能障碍可能导致肥胖相关的代谢紊乱，如 2 型糖尿病（T2DM）。由于线粒体是褪黑素作用的靶点，因此本研究的目的是研究褪黑素对 Zücker 糖尿病肥胖（ZDF）大鼠白色（WAT）和米色腹股沟脂肪组织中线粒体功能的影响，这是肥胖相关 T2DM 的模型。在这个实验模型中，褪黑素可以减轻肥胖并改善代谢谱。在 6 周龄时，ZDF 大鼠和瘦的同窝仔鼠（ZL）被分为两组，每组由四只大鼠组成：对照组（C-ZDF 和 C-ZL）和用饮用水中的口服褪黑素（10mg/kg/天）治疗 6 周（M-ZDF 和 M-ZL）。治疗期结束后，处死动物，分离组织，并评估分离细胞器中的线粒体功能。褪黑素增加了来自瘦（增加 26.5%，P<0.01）和肥胖（增加 34.5%，P<0.01）大鼠白色脂肪的线粒体呼吸控制率（RCR），主要通过降低呼吸质子泄漏成分（状态 4）（ZL 降低 28%，P<0.01 和 ZDF 降低 35%，P<0.01）。然而，褪黑素处理降低了瘦（降低 7%，P<0.05）和肥胖（降低 13%，P<0.05）大鼠米色线粒体的 RCR，通过维持高解偶联呼吸率。褪黑素还通过降低亚硝酸盐水平和增加超氧化物歧化酶活性来降低线粒体氧化状态。此外，褪黑素处理还在来自瘦和肥胖大鼠的两种脂肪（白色和米色）的分离线粒体中，严重抑制了 Ca 诱导的 mPTP 开放。这些结果表明，慢性口服褪黑素可改善线粒体呼吸，并降低白色和米色脂肪细胞的氧化状态和易感性凋亡。这些褪黑素作用有助于预防线粒体功能障碍，并因此改善 ZDF 大鼠肥胖相关的代谢紊乱，如糖尿病和血脂异常。
