| Project Detail |
Obesity and type 2 diabetes continuously progress worldwide, compromising healthy aging. Deregulated endogenous glucose production (EGP) is involved in hyperglycemia and its complications. Among the 3 organs (liver, kidney, intestine) contributing to EGP, I uncovered with my team that intestinal gluconeogenesis (IGN) has the capacity to interfere in the control of energy homeostasis. Indeed, intestinal glucose initiates a gut-brain circuit controlling both body weight and glucose production by the liver, the strongest quantitative contributor to EGP. Intestinal gluconeogenesis is, thus, a novel target to control obesity and diabetes.
The IGN project has 3 objectives:
Understand: is dedicated to elucidating the neural mechanisms by which IGN is sensed and send its signals to the brain. Our data suggested that glucose receptor sodium-glucose co-transporter 3 (SGLT3) could be the peripheral sensor of IGN. Moreover, we showed that the neuromediator calcitonin gene-related peptide alpha (CGRPa) is mandatory for the IGN signal. I will use original mouse models to map the SGLT3-neuron connection to the brain and define the role of CGRPa.
Explore: aims at expanding the scope of IGN to the networking of hypothalamus during the neonatal period. I will assess whether the surge of IGN occurring during the neonatal period may control the development of neuronal connections between the hypothalamic nuclei, to ensure an optimal control of energy homeostasis in adult, as previously observed for the neonatal surge of the hormone leptin.
Take advantage: aims at identifying novel metabolites able to activate IGN and test them as beneficial modulators of energy homeostasis under unbalanced nutrition. This will pave the way to novel therapeutic approaches of metabolic diseases based on IGN.
Thus, the IGN project should lead to a better understanding of metabolic control and offer new perspectives for preventing metabolic diseases and maintaining healthy ageing. |
