Intestinal Gluconeogenesis: Emerging Regulator of Energy Homeostasis

Introduction

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.

Gut-Brain Circuit

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.

Project Objectives

The IGN project has 3 objectives:

1. Understand

This objective is dedicated to elucidating the neural mechanisms by which IGN is sensed and sends 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.

2. Explore

This objective aims at expanding the scope of IGN to the networking of the 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 adulthood, as previously observed for the neonatal surge of the hormone leptin.

3. Take Advantage

This objective 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 for metabolic diseases based on IGN.

Conclusion

Thus, the IGN project should lead to a better understanding of metabolic control and offer new perspectives for preventing metabolic diseases and maintaining healthy aging.