Project description
A novel role for the intestine in metabolic control
Obesity and type 2 diabetes are characterised by deregulated endogenous glucose production (EGP), causing hyperglycemia and concomitant complications. Although the liver, kidney and intestine contribute to EGP, recent evidence indicates that production of glucose in the intestine forms a gut-brain circuit affecting body weight and liver glucose production. Funded by the European Research Council, the IGN project therefore proposes intestinal gluconeogenesis as a novel target against obesity and diabetes. Researchers aim to elucidate the neural mechanisms of intestinal gluconeogenesis and identify metabolites to modulate energy balance. This research promises to advance metabolic disease prevention and promote healthy ageing.
Objective
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.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomolecules
- medical and health sciencesclinical medicineendocrinologydiabetes
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensors
- medical and health sciencesbasic medicinephysiologyhomeostasis
- medical and health scienceshealth sciencesnutritionobesity
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
75794 Paris
France