Obesity and diabetes are characterized by deregulations of endogenous glucose production. Three organs, the liver, kidney and intestine can produce glucose in the blood because they have the key enzyme: glucose-6 phosphatase (G6Pase). While hepatic glucose production is deleterious, intestinal glucose production is beneficial, since it sends a signal to the brain and exerts anti-obesity and anti-diabetes mediated by the hypothalamus. This especially takes place when intestinal glucose production is induced by diets enriched in protein or in soluble fiber fermented by the gut microbiota. We here want to make the proof of concept that intestinal glucose production per se may exert beneficial effects, i.e. regardless of any nutritional regulation. With this aim, we shall characterize new original animal models developed by the laboratory. We shall study the protection of mice constitutively overexpressing intestinal G6Pase against the development of obesity and diabetes induced by a deleterious “westernized” diet (rich in fat and sucrose). Using a procedure of overexpression inducible (by tamoxifen), we shall evaluate the capacity of intestinal glucose production to combat obesity and the deregulation of glucose control under conditions of pre-established obesity/diabetes. As an alternative to mimic intestinal glucose production and its benefits, we shall study the effect of infusions of glucose into the portal vein (via a catheter) in rodent models of obesity, pre-diabetes or diabetes. This will include genetic models of obesity/diabetes, such as Ob/Ob and Db/Db mice, and the Zucker Diabetic Fatty rat. In parallel, we shall deepen the molecular mechanisms involved in the central signal initiated by intestinal glucose production. This will include the identification of the nervous routes of transmission of the portal glucose signal, using an approach of electrophysiology on isolated gastrointestinal nerves and on central nuclei in vivo, and of the molecular mechanisms taking place in the hypothalamus, focusing on the original hypothesis of an interaction between the portal glucose signal and the hypothalamic leptin signalling. This will be studied by comparing the mechanisms taking place in mice deficient in intestinal G6Pase and mice overexpressing intestinal G6Pase. A better knowledge of the mechanisms initiated by intestinal glucose production and its metabolic benefits could pave the way for future approaches of prevention or treatment of metabolic diseases.