Abstract
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.
Highlights
Mitochondrial dysfunction is a main mechanism underlying insulin resistance in obesity and type 2 diabetes mellitus (T2DM) [1,2]
(mitochondria from brown adipose tissues (BAT) of white and beige fat depots of C-Zücker lean (ZL) and C-Zücker diabetic fatty (ZDF) rats) was challenged with calcium in the presence of cyclosporine A (CsA); and (4) melatonin + CsA challenged with calcium in the presence of CsA. mitochondrial permeability transition pore (mPTP) opening was measured from signals over time and expressed as the area under the curve (AUC), and four replicates were made for each sample
As shown i tochondria isolated from both melatonin-treated ZL and ZDF anim reduced oxygen flux in state 3 compared with untreated controls in of ZL and ZDF phenotypes
Summary
Mitochondrial dysfunction is a main mechanism underlying insulin resistance in obesity and type 2 diabetes mellitus (T2DM) [1,2]. Previous reports have documented that melatonin enhances mitochondrial respiration and alleviates oxidative stress in different pathological conditions and in a broad variety of organs and tissues [14,29], including the brain [30,31] and liver [32,33,34,35,36], as well as cardiac [37,38,39] and skeletal muscle [40]. Data from our laboratory showed that melatonin improved mitochondrial function of different organs and tissues like liver, kidney, and inguinal white adipose tissue in diabesity conditions in Zücker diabetic fatty (ZDF) animals [20,36,43]. The present work investigated the effect of chronic oral melatonin administration on the mitochondrial function of BAT isolated from obese–diabetic ZDF rats (a well-established model of metabolic syndrome and T2DM) and their Zücker lean (ZL) littermates
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