Background:Diet-induced inflammation, particularly from high-fat (HF) diet, is widely recognized as a contributing factor to neurological impairments and neurodegenerative disorders. Melanotan-II (MT-II), which targets and activates melanotropin receptors, may exert neuromodulatory and anti-inflammatory effects. Yet, the role of melanotropins in countering the diet-induced effects remain largely unexplored.Objective:The study investigates the possible relationship among diet, Melanotan-II (MT-II), a melanotropin receptor analog, and the behavior of zebrafish (Danio rerio).Methods:Zebrafish were fed with HF diet over a short period representing approximately 1% of their lifespan.Behavioral comparisons were made between zebrafish on a high-fat diet and those on a control diet.The ability of MT-II to reverse diet-related changes was investigated.Results:Zebrafish subjected to a high-fat diet exhibited significant impairments in recognition memory, increased anxiety, and reduced exploratory behaviors within three weeks.However, MT-II treatment mitigated these deficits, making the behavior of the zebrafish similar to zebrafish on a standard diet.Conclusions:This study demonstrated for the first time the efficacy of MT-II in reversing cognitive and emotional impairment caused by a high-fat diet. This may suggest a therapeutic application of melanotropin receptor targeting in the treatment of diet-related inflammation.