Dose-Dependent Effect of Melatonin on BAT Thermogenesis in Zücker Diabetic Fatty Rat: Future Clinical Implications for Obesity

Abstract

Experimental data have revealed that melatonin at high doses reduced obesity and improved metabolic outcomes in experimental models of obesity, mainly by enhancing brown adipose tissue (BAT) thermogenesis. A potential dose-response relationship has yet to be performed to translate these promising findings into potential clinical therapy. This study aimed to assess the effects of different doses of melatonin on interscapular BAT (iBAT) thermogenic capacity in Zücker diabetic fatty (ZDF) rats. At 6 wk of age, male ZDF rats were divided into four groups (n = 4 per group): control and those treated with different doses of melatonin (0.1, 1, and 10 mg/kg of body weight) in their drinking water for 6 wk. Body weight (BW) was significantly decreased at doses of 1 and 10 mg/kg of melatonin, but not at 0.1 mg/kg compared with the control, with a similar rate of BW decrease being reached at the dose of 1 mg/kg (by ~11%) and 10 mg/kg (by ~12%). This effect was associated with a dose-dependent increase in the thermal response to the baseline condition or acute cold challenge in the interscapular area measurable by infrared thermography, with the highest thermal response being recorded at the 10 mg/kg dose. Upon histology, melatonin treatment markedly restored the typical brownish appearance of the tissue and promoted a shift in size distribution toward smaller adipocytes in a dose-dependent fashion, with the most pronounced brownish phenotype being observed at 10 mg/kg of melatonin. As a hallmark of thermogenesis, the protein level of uncoupled protein 1 (UCP1) from immunofluorescence and Western blot analysis increased significantly and dose-dependently at all three doses of melatonin, reaching the highest level at the dose of 10 mg/kg. Likewise, all three doses of melatonin modulated iBAT mitochondrial dynamics by increasing protein expression of the optic atrophy protein type 1 (OPA1) fusion marker and decreasing that of the dynamin-related protein1 (DRP1) fission marker, again dose-dependently, with the highest and lowest expression levels, respectively, being reached at the 10 mg/kg dose. These findings highlight for the first time the relevance of the dose-dependency of melatonin toward BW control and BAT thermogenic activation, which may have potential therapeutic implications for the treatment of obesity. To clinically apply the potential therapeutic of melatonin for obesity, we consider that the effective animal doses that should be extrapolated to obese individuals may be within the dose range of 1 to 10 mg/kg.

Effects of exogenous melatonin on body mass and thermogenesis in red‐backed vole (Eothenomys miletus) between Kunming and Dali regions

“…Ability of NST in BAT depends on the UCP1 content (Buonfiglio et al, 2018; Halpern et al, 2020). MEL enhanced UCP1 content in P. sungorus (Ryu et al, 2018), Wistar rats (Halpern et al, 2020; Mendes et al, 2021), Zucker rats (Aouichat et al, 2022; Fernández Vázquez et al, 2018; Jiménez‐Aranda et al, 2013) and C57BL/6 J mice (L. Xu et al, 2022). Thermogenic activity of BAT after MEL injection in E. miletus in the present study was similar to results which were mentioned above, although there was no significant difference between the BAT mass of MEL group and SAL group in both regions, the UCP1 content was significantly increased in MEL group, which favored enhanced NST, consistent with the higher NST in E. miletus .…”

“…In many mammals, MEL is only secreted at night by pineal gland, and its secretion process is directly related to the hour of darkness, thus transducing changes in photoperiod length into neuroendocrine signals that trigger seasonal adaptation responses (Buonfiglio et al, 2018). MEL plays an important role in regulating physiological processes, such as food intake, body mass and thermogenesis (Aouichat et al, 2022; Bartness & Wade, 1985; Buonfiglio et al, 2018; Hall & Lynch, 1985; Heldmaier et al, 1981; Mendes et al, 2021). MEL injection reduced body mass and food intake in Phodopus sungorus (Ryu et al, 2018), Mesocricetus auratus gained food intake and body mass during MEL treatment (Bartness & Wade, 1984).…”

Melatonin in energy control: Circadian time‐giver and homeostatic monitor

“…70 In addition, it should be mentioned that non-shivering thermogenesis of brown adipose tissue can be activated by treatment with dose-dependent exogenous melatonin. 79 Under certain circumstances, like cold exposure, white adipocytes can turn beige due to enhanced metabolic capacity. Of note, melatonin treatment increases this beginning process in white adipose tissue, which may also limit body mass gain.…”

“…This effect may be partly due to increased oxygen consumption by white adipose tissue, as demonstrated by the calorimetric study of isolated adipocytes from high‐fat‐fed mice supplemented with nocturnal melatonin 70 . In addition, it should be mentioned that non‐shivering thermogenesis of brown adipose tissue can be activated by treatment with dose‐dependent exogenous melatonin 79 . Under certain circumstances, like cold exposure, white adipocytes can turn beige due to enhanced metabolic capacity.…”

The Influence of Antioxidants on Oxidative Stress-Induced Vascular Aging in Obesity

“…Melatonin is a pineal hormone involved in circadian rhythm regulation and lipid metabolism. Along with its antioxidant and anti-inflammatory role, melatonin can convert WAT to BAT and reduce obesity by increasing the thermogenesis of BAT in obese rats [ 90 , 94 , 95 ]. Therefore, it can be a therapeutic target for improving obesity and oxidative stress, simultaneously.…”