Developing novel drugs/targets remains a major effort toward controlling obesity-related type 2 diabetes (diabesity). Melatonin controls obesity and improves glucose homeostasis in rodents, mainly via the thermogenic effects of increasing the amount of brown adipose tissue (BAT) and increases in mitochondrial mass, amount of UCP1 protein, and thermogenic capacity. Importantly, mitochondria are widely known as a therapeutic target of melatonin; however, direct evidence of melatonin on the function of mitochondria from BAT and the mechanistic pathways underlying these effects remains lacking. This study investigated the effects of melatonin on mitochondrial functions in BAT of Zücker diabetic fatty (ZDF) rats, which are considered a model of obesity-related type 2 diabetes mellitus (T2DM). At five weeks of age, Zücker lean (ZL) and ZDF rats were subdivided into two groups, consisting of control and treated with oral melatonin for six weeks. Mitochondria were isolated from BAT of animals from both groups, using subcellular fractionation techniques, followed by measurement of several mitochondrial parameters, including respiratory control ratio (RCR), phosphorylation coefficient (ADP/O ratio), ATP production, level of mitochondrial nitrites, superoxide dismutase activity, and alteration in the mitochondrial permeability transition pore (mPTP). Interestingly, melatonin increased RCR in mitochondria from brown fat of both ZL and ZDF rats through the reduction of the proton leak component of respiration (state 4). In addition, melatonin improved the ADP/O ratio in obese rats and augmented ATP production in lean rats. Further, melatonin reduced mitochondrial nitrosative and oxidative status by decreasing nitrite levels and increasing superoxide dismutase activity in both groups, as well as inhibited mPTP in mitochondria isolated from brown fat. Taken together, the present data revealed that chronic oral administration of melatonin improved mitochondrial respiration in brown adipocytes, while decreasing oxidative and nitrosative stress and susceptibility of adipocytes to apoptosis in ZDF rats, suggesting a beneficial use in the treatment of diabesity. Further research regarding the molecular mechanisms underlying the effects of melatonin on diabesity is warranted.

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褪黑激素增强肥胖-糖尿病大鼠棕色脂肪组织的线粒体功能

开发新的药物/靶点仍然是控制与肥胖相关的 2 型糖尿病（糖尿病）的主要努力。褪黑激素主要通过增加棕色脂肪组织 (BAT) 的数量和线粒体质量、UCP1 蛋白的数量和产热能力的产热效应来控制肥胖并改善啮齿动物的葡萄糖稳态。重要的是，线粒体被广泛认为是褪黑激素的治疗​​靶点。然而，褪黑激素对来自 BAT 的线粒体功能的直接证据以及这些影响背后的机制途径仍然缺乏。这项研究调查了褪黑激素对 Zücker 糖尿病脂肪 (ZDF) 大鼠 BAT 线粒体功能的影响，Zücker 糖尿病脂肪 (ZDF) 大鼠被认为是肥胖相关的 2 型糖尿病 (T2DM) 模型。在五周大的时候，Zücker Lean (ZL) 和 ZDF 大鼠分为两组，对照组和口服褪黑激素治疗六周。使用亚细胞分离技术从两组动物的 BAT 中分离线粒体，然后测量几个线粒体参数，包括呼吸控制比 (RCR)、磷酸化系数 (ADP/O 比)、ATP 产生、线粒体亚硝酸盐水平、超氧化物歧化酶活性和线粒体通透性转换孔 (mPTP) 的改变。有趣的是，褪黑激素通过减少呼吸的质子泄漏成分增加了 ZL 和 ZDF 大鼠棕色脂肪线粒体中的 RCR（状态 4）。此外，褪黑激素改善了肥胖大鼠的 ADP/O 比率并增加了瘦大鼠的 ATP 产生。更远，褪黑激素通过降低两组中亚硝酸盐水平和增加超氧化物歧化酶活性来降低线粒体亚硝化和氧化状态，并抑制从棕色脂肪中分离出的线粒体中的 mPTP。综上所述，目前的数据表明，长期口服褪黑激素可改善棕色脂肪细胞的线粒体呼吸，同时降低氧化和亚硝化应激以及脂肪细胞对 ZDF 大鼠细胞凋亡的易感性，表明其在治疗糖尿病方面具有有益的用途。需要进一步研究褪黑激素对糖尿病影响的分子机制。目前的数据显示，长期口服褪黑激素可改善棕色脂肪细胞的线粒体呼吸，同时降低氧化和亚硝化应激以及脂肪细胞对 ZDF 大鼠凋亡的易感性，表明其在治疗糖尿病方面具有有益的用途。需要进一步研究褪黑激素对糖尿病影响的分子机制。目前的数据显示，长期口服褪黑激素可改善棕色脂肪细胞的线粒体呼吸，同时降低氧化和亚硝化应激以及脂肪细胞对 ZDF 大鼠凋亡的易感性，表明其在治疗糖尿病方面具有有益的用途。需要进一步研究褪黑激素对糖尿病影响的分子机制。