Intestinal Gluconeogenesis: Emerging Regulator of Energy Homeostasis

Project Information

IGN

Grant agreement ID: 101097330

DOI

10.3030/101097330

EC signature date 20 June 2023

Start date 1 October 2023

End date 30 September 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 1 - IGN (Intestinal Gluconeogenesis: Emerging Regulator of Energy Homeostasis)

Reporting period: 2023-10-01 to 2026-03-31

Summary of the context and overall objectives of the project

The project is part of efforts to understand and treat obesity and diabetes. Among the three organs capable of producing glucose in the blood (the liver, kidneys, and intestine), we have discovered that the glucose produced by the intestine after complete digestion of a meal (a function called intestinal gluconeogenesis or IGN) is detected by nerves around the intestine, which then transmit a signal to the brain. The brain responds by reducing feelings of hunger (thus having anti-obesity effects) and glucose production by the liver (thus having anti-diabetes effects).
The project has three objectives:
1) Objective 1: Understand the neural connection between the detection of glucose produced by the intestine to the brain, i.e. identify the nerves involved and their site of impact in the brain. In this part, we also want to identify the molecule that transforms glucose detection into a nervous signal and the molecules within the neurons that are involved.
2) Objective 2: It has been shown that the neonatal period is very important for the development of neural networks in the brain that control body weight regulation and predisposition to diabetes in adulthood. Since IGN is increased during this period, we want to know whether it contributes to the development of these neural networks. We will also test whether its induction can strengthen connections and protect offspring from obesity when the mother is fed a high-calorie diet, and conversely, whether offspring are predisposed to obesity and diabetes when IGN is deficient during breastfeeding.
3) Objective 3: In the third part, we want to identify molecules that would be capable of activating IGN and its beneficial effects, with the aim of finding new therapeutic approaches. We will conduct research on plasma molecules that would be increased under different nutritional conditions of IGN induction (particularly diets rich in protein or fiber). Initially, the molecules identified will be tested in cell cultures to evaluate their induction of the IGN. Next, the molecules that induce it will be tested for their potential protective effect on normal mice fed a high-calorie diet. We will prove that IGN is involved in these effects by conducting the same experiments on mice from which we will have removed IGN through genetic manipulation.
This project could therefore lead to a better understanding of the anti-obesity and anti-diabetes processes of gut-brain nerve signals and contribute to the emergence of new treatments for obesity and diabetes.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Objective 1 of the project requires obtaining new mouse models. This takes a lot of time. However, we have now obtained the first models, which are currently being crossbred in order to produce enough mice to carry out the studies. In the meantime, using mice already available and new microsurgical methods, we have determined that a part of the brain that is very important in food intake (called the parabrachial nucleus) is needed in the IGN signal, which implies that the spinal cord is involved in signal transmission, rather than the vagus nerve.

For objective 2, we have demonstrated, in line with our hypothesis, that the IGN signal during the neonatal period controls the formation of neural networks that indeed regulate food intake. More specifically, these nerworks involve connections between two types of neurons in a brain area called the arcuate nucleus. One type of neuron activates hunger, while the other inhibits it. These connections extend to a more internal part of the brain, where hunger and fat storage are actually controlled. In addition, we have established that animals that have had neonatal IGN activation are protected from obesity and diabetes when fed a high-fat diet in adulthood. This study has been published in a renowned international journal.

As part of objective 3, non-targeted studies dedicated to the search for new molecules capable of regulating IGN have been conducted. The results are currently being analyzed. Meanwhile, we have continued targeted studies on already known molecules. We have identified a new molecule capable of inducing IGN and protecting against obesity and diabetes via IGN (i.e. mice lacking this function show no effect of this molecule). This molecule has been submitted for patent application for future use in the treatment of obesity and diabetes. We have also shown that several members of another class of molecules are also capable of activating IGN gene expression in cell cultures. Confirmatory experiments in mice are currently underway.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

In aim 2, the demonstration that IGN might be a lever to act on metabolic programming of neurons involved in the control of body weight significantly advances the field beyond the state-of-the-art. Indeed, until now, it had only been shown that some hormones could control the development of the brain during this period . Here, we demonstrate that a physiological function dependent on the metabolism of nutrients may also play a crucial role in the healthy control of body weight and diabetes of the offspring at adult age.

In aim 3, that a new molecule capable of controlling diabetes and obesity could do so through the activation of IGN put forward IGN as a new potential lever to positively interfere in energy homeostasis. This is an important breakthrough in the field of obesity and diabetes. This also significantly advances the field beyond state-of-the-art.

In conclusion, the project’s global impact could result in a novel approach in the control of obesity and diabetes, likely to lead to a novel treatment of these serious metabolic diseases.