Obesity and its associated diseases, such as type 2 diabetes, are a worldwide health concern. The most effective and durable therapies for the treatment of obesity nowadays involve surgical rather than behavioral or pharmacological interventions. Patients that undergo bariatric surgery not only lose weight, but also have rapid diabetes remission. The mechanisms leading to these beneficial metabolic changes remain largely unclear and are the focus of intense research. Besides, despite its efficacy, surgery is not a suitable therapeutic option for many obese subjects. Thus, the understanding of the underlying biological mechanisms responsible for the surgery-induced weight loss and metabolic improvements is crucial so that affected pathways can be targeted in a less-invasive, more specific manner. Bile acids have been recently recognized as an important molecular underpinning for the beneficial effects of bariatric surgery. Besides, bile acids are known to exert pleiotropic effects in peripheral organs where they regulate energy expenditure, glucose and lipid metabolism. Bile acids exert most of these metabolic effects by engaging the membrane-bound G protein-coupled bile acid receptor 1, also known as the Takeda G protein-coupled receptor 5 (TGR5), and the nuclear Farnesoid X receptor (FXR). So far, however, all studies investigating bile acids function in energy balance and metabolism have exclusively focused on their action at peripheral level. Based on solid preliminary data, here we put forward the original hypothesis that there is a long-range, hypothalamic control of bile acids effects on metabolism, which involves signaling through hypothalamic TGR5 and FXR. Thus, the main objectives of the BABrain project are: 1) to dissect the role of hypothalamic bile acids-TGR5 and FXR signaling in metabolic control; 2) to define the role of hypothalamic bile acids signaling in determining the beneficial effects of bariatric surgery. In order to reach these objectives, we will use a multidisciplinary approach including pharmacological, genetic, behavioral, metabolic and molecular studies combined with the use of animal models of diet-induced obesity (DIO) and bariatric surgery. In particular, we propose to characterize the metabolic effects of central chronic administration of TGR5 or FXR agonists (including specific bile acids) in diet-induced obese mice by performing a complete behavioral and metabolic phenotyping. “Smart” TGR5 agonists will be also tested for their ability to impact organism’s metabolic responses through a tightly controlled and selective activation of brain TGR5 receptors. Effects of TGR5 and FXR signaling on hypothalamic circuits will be investigated by using chemogenetics and ad hoc genetic animal models. Involvement of specific mechanisms underlying the phenotype, such as modulation of the autonomous nervous system and intestinal gluconeogenesis, as well as changes in bile acids metabolism and of the expression of specific molecular targets will be investigated using biochemistry, pharmacology, RNA sequencing and by employing specific genetic models. Finally, in order to evaluate the causative role of hypothalamic TGR5 or FXR in the phenotype obtained by chronic central administration of TGR5 or FXR agonists or after bariatric surgery, hypothalamic TGR5 or FXR expression will be silenced using Cre/lox and/or ShRNA-AAV strategies. We expect that the obtained findings will unambiguously establish the role of hypothalamic bile acids signaling in modulating metabolic responses and in determining potential beneficial effects of bile acids in metabolic disease.