Neural Control of Appetite and Metabolism by Neural Cell Adhesion Molecule – NCAM2

Context. Occidental countries have to face a dramatic expansion of metabolic diseases, including obesity and diabetes, representing a major health burden in industrialized societies. The rapid increase in prevalence of these metabolic diseases is likely due to changes in environment and lifestyle, generating “obesogenic” conditions linked to an excessive energy intake. In healthy animals, food intake is permanently adjusted to fit with the cumulative energy expenditure. This remarkable energy stability is finely tuned by the central nervous system after a permanent monitoring of numerous metabolic signals within discrete brain areas. A thorough understanding of the neural mechanisms controlling food intake and metabolism will definitely help finding ways to stop the expansion of metabolic diseases. The hypothalamus, which ensures long-term stability of the inner milieu, is of major importance in the control of energy balance. Interestingly, the hypothalamus remains “plastic” in the adulthood, meaning that neuronal networks in this structure can undergo functional or morphological remodeling aimed at integrating environmental and internal conditions. Interestingly, genome-wide association studies in human have reported a strong association between high body-mass index and polymorphic loci whose genes are highly expressed in the brain and involved in neuronal plasticity. Moreover, haploinsufficiency of BDNF, a factor that mediates brain plasticity, is associated with childhood-onset obesity. These studies suggest that brain plasticity may play a role in regulating energy balance in humans. Indeed, we recently showed that plasticity of feeding circuits is required for the homeostatic regulation of food intake in mice. We identified the polysialic acid (PSA), a complex sugar modulating cell-to-cell interaction, as a mediator of the plasticity of feeding circuits. Furthermore, genetic or pharmacological removing of PSA is obesogenic. We propose to pursue our work on neural control of appetite and metabolism in mice with a powerful nutrigenomic approach to uncover molecular bases of PSA biosynthesis at the chromatin level.

Objectives of the proposal and expected results. Biological explanation underlying individual predisposition to obesity and its complications are still lacking. Since PSA-dependent hypothalamic plasticity is required for homeostatic regulation of food intake, we postulate that low individual capacity of neuronal rewiring due to low hypothalamic PSA level could explain metabolic inflexibility, intolerance to dietary fat, and vulnerability to diet-induced obesity (DIO). Thus, main objectives of the project are to determine the link between hypothalamic PSA level and obesity, and to uncover molecular mechanisms underlying PSA-triggered homeostatic control of energy balance. We expect to show that low hypothalamic PSA level predisposes to DIO, and that PSA supplementation is a conceptual basis for a therapy to promote loss of weight during obesity. Next, we want to describe the chromatin-remodeling events that are crucial for PSA synthesis and for regulation of food intake. This fundamental analysis is a prerequisite allowing us to identify exhaustively all the signaling pathways activated in the hypothalamus during metabolic imbalance. We will determine whether the methylation state of St8sia4, a gene involved in polysialylation, is linked to predisposition to DIO.

Methods. The team has expertise in fields of Nutrition, Metabolism and Neurosciences, and skills from behavior to molecule analysis to complete the objectives. This project relies on the use of three specific fronts of science: (i) state-of-the-art molecular biology to perform original and accurate investigation of molecular processes stimulated during a metabolic switch (i.e. in vivo chromatin immuno-precipitation, proteomic); (ii) functional exploration of energy metabolism; and (iii) gene and pharmacological manipulation in the adult hypothalamus.