Obesity is a worldwide epidemic leading to many health concerns and is a risk factor for the development of type 2 diabetes. In Reunion Island, obesity and diabetes are widely spread among the population. Both diseases share several metabolic disorders and have been recently implicated in deteriorating brain health, contributing to cognitive impairments. The mechanisms behind the onset of altered brain homeostasis are not well understood. Besides, no therapy has yet been established to prevent brain disruptions. The aim of this thesis is to study the impact of obesity/prediabetes on brain homeostasis and cerebral plasticity, and then to alleviate these deleterious effects using medicinal plants from Reunion Island. To this end, we set up a diet-induced obesity (DIO) protocol in zebrafish (Danio rerio). Zebrafish recently emerges as a relevant model to mimic metabolic diseases (obesity and diabetes), and to investigate brain homeostasis and plasticity (i.e., blood-brain barrier (BBB) and neurogenesis). Our DIO model, established by overfeeding adult zebrafish for 4 weeks, resulted in metabolic disorders and loss of central nervous system (CNS) homeostasis. Indeed, DIO fish displayed increased body weight and body mass index (BMI), hyperglycemia, liver steatosis and disturbed redox balance. In the central nervous system, overfeeding led to BBB leakage, neuro-inflammation, cerebral oxidative stress and decreased neurogenesis. As well, a change in the locomotor behavior was observed in obese fish. In a next step, we tested the potential beneficial properties of two Reunionese plants registered in the French pharmacopeia: Antirhea borbonica (A. borbonica) and Psiloxylon mauritianum (P. mauritianum). Both plants were traditionally used for their positive effects on metabolic disruptions as “anti-diabetic” effects for A. borbonica and “anti-lipidemic” for P. mauritianum. However, the scientific data supporting these properties are lacking. First, the chemical analysis of aqueous extract of A. borbonica and P. mauritianum revealed their abundance in polyphenols, correlated to their antioxidant properties. LC-MS/MS analysis was used to determine the nature of the polyphenolic compounds in each extract. Next, we performed toxicity assays using OECD guidelines 36 (Organization for Economic Co-operation and Development) (OECD, 2013) and defined a maximum non-toxic concentration for each extract. The overnight treatment with aqueous extract of A. borbonica (0.5g/L) during the DIO protocol demonstrated its preventive properties against the deleterious effects on the CNS induced by overfeeding. Indeed, A. borbonica preserved the BBB function, prevented the increase in cerebral oxidative stress, neuro-inflammation and normalized neurogenesis. Similarly, the aqueous extract of P. mauritianum (0.25 g/L) was tested on adult DIO zebrafish and in high-fat diet (HFD) treated larvae. The treatment avoided lipid accumulation in HFD larvae. It also prevented body weight increase, BMI, hyperglycemia and liver steatosis in adult DIO zebrafish. Furthermore, brain homeostasis seems to be preserved probably through P. mauritianum anti-weight gain properties. We suggested that P. mauritianum could significantly affect lipid absorption and metabolism possibly through the modulation of gut microbiota. In conclusion, during this thesis, we have developed a simple and rapid overfeeding (DIO) model inducing peripheral and CNS disruptions similar to those encountered in mammals. For the first time, we studied the toxicity of aqueous extract of the two medicinal plants A. borbonica and P. mauritianum. We confirmed their beneficial effects on different metabolic parameters and on the brain using zebrafish model of obesity and prediabetes. Together, these data highlight the use of zebrafish to mimic metabolic diseases and to screen the beneficial properties of medicinal plants extracts.