High fat diet (HFD) chronic intake induces metabolic syndrome in mice, characterized by a body weight increase and insulin resistance (IR). Furthermore, non-alcoholic fatty liver disease (NAFLD) is strongly linked to metabolic syndrome appearance. Obesity is a risk factor in the development of neurodegenerative diseases, neuropsychiatric disorders and is associated with cognitive decline. DREAM/kchip3/calsenilin (DREAM) is a multifunctional protein that belongs to the neuronal Ca2+ sensor family. Previous studies have demonstrated the relevance of DREAM in nociception and in learning and memory processes. DREAM protein can be inhibited pharmacologically by repaglinide (RPG), an oral drug commercialized as an insulinotropic agent. In the present study we characterize the consequences of DREAM, genetic (gen KO) or pharmacologic (chronic repaglinide oral administration), inhibition in the molecular, cellular, metabolic and behavioural alterations caused by HFD (21% energy taken from fat) intake in C57black6 mice. To this aim, we developed H-E histological assays in fatty tissues; body weight monitoring and blood glucose tests; and behaviroural tests. Our results showed that chronic pharmacological and genetic DREAM inhibition block the metabolic syndrome and NAFLD development, and both of its neurologic comorbidity symptoms: the anxiety-related behaviour, and the cognition deficiency. Also, pharmacologic DREAM inhibition when metabolic syndrome is established did not affect metabolic parameter but improved metabolic syndrome-related neurologic alterations. Therefore, in this study we demonstrate: DREAM inhibition may be a potential treatment to restore neurological symptoms related with metabolic syndrome; and to block metabolic syndrome and NAFLD induced by HFD intake.