Dose-dependent beneficial effect of melatonin on obesity; interaction of melatonin and leptin

Although numerous studies have noted leptin’s role in obesity, there are still important mechanisms insights that need to be elucidated. Disturbed leptin production is associated with eating disorders, leading to alter food intake and energy expenditure. Proper regulation of protein homeostasis is critical for metabolic diseases such as obesity. Thus, the purpose of the present work was to study the unfolded protein response, which is implicated in the alleviation of endoplasmic reticulum stress-dependent dysregulation of nutritional status. We studied the effect of leptin deficiency on liver, brain and skeletal muscle tissues in obese (ob/ob) mice and the actions of a daily melatonin administration, as a possible treatment. Our findings showed that the leptin-deficient mice presented tissue-specific alterations of the three adaptive unfolded protein responses. ATF6α arm is strongly activated in all of them, indicating a deregulated lipid metabolism by the lack of leptin. Likewise, melatonin also alleviates unfolded protein response in a tissue-specific manner, acting mainly in the restoration of this disturbed ATF6α pathway. These findings support the use of melatonin as a potential therapeutic treatment against leptin-associated disorders.