Physiopathologies cardiométaboliques associées à l'obésité : mécanismes sous-jacents et thérapie nutritionnelle

The digestive tract and liver interact continuously, not only through anatomical connections, but also through physiological / functional links. The imbalance of the intestine-liver axis is increasingly emerging as a key factor in cardiometabolic disorders (CMD), namely obesity, metabolic syndrome, type 2 diabetes, and non alcoholic fatty liver disease (NAFLD), for which prevalence remains alarmingly high, molecular mechanisms are poorly understood, and treatments are largely inefficient.  The central hypothesis of this research project is that the combination of genetic and nutritional abnormalities affect intestinal insulin sensitivity, leading to overproduction of chylomicrons, dyslipidemia, systemic insulin resistance and dysregulated intestine-liver axis. In this situation, the liver develops progressive NAFLD, implicating several intrinsic metabolic pathways and mechanisms, including oxidative stress, inflammation and insulin resistance. In contrast, functional foods, such as omega-3 polyunsaturated fatty acids (n-3 PUFA), may have beneficial effects by targeting several pathogenic pathways.  The central objective of this thesis is to: (i) Demonstrate that genes coding for key intestinal proteins associated with lipid transport, as is the case with Sar1b GTPase, can interact with the nutritional environment to produce obesity and CMD, including hepatic steatosis; (ii) explore the mechanisms underlying NAFLD; and (iii) identify the effects and therapeutic targets of n-3 PUFA. These objectives will be supported by a critical review on metabolic syndrome and NAFLD in order to dissect their strengths and weaknesses for the benefit of the scientific community.  For these purposes, we used genetically engineered animal and cell models, chronic exposure of animals to high-fat diets, liver tissue specimens obtained during bariatric surgery of morbidly obese patients, and treatment of obese NAFLD adolescents with n-3 PUFA.  All of our experiments supported our hypotheses and highlighted the following concepts and mechanisms: (i) The abundance of a crucial gene (notably Sar1b GTPase) in the intestine, in synergy with an obesogenic diet, disrupts local homeostasis and leads to CMD, challenging even the intestine-liver axis; (ii) Developmental causes of NAFLD include disturbances of fatty acid metabolism, redox and inflammatory status, insulin sensitivity, metabolic pathways (lipogenesis, β-oxidation, gluconeogenesis), and expression of transcription factors; and (iii) n-3 PUFA represent a robust therapeutic arsenal of CMD, including NAFLD, by acting on several pathogenic targets.  Overall, our results show the undeniable role of the intestine, as an insulin-sensitive organ, interacting closely with obesogenic food, and capable of triggering CMD, including perturbations of the intestine-liver axis. Several mechanisms governing metabolic disorders have been unveiled by our work. In addition, our clinical studies have pointed to the therapeutic potential of n-3 PUFA involved in many regulatory processes, including oxidative stress and inflammation.

Keyphrases: Nutrition, NAFLD, Inflammation, Acides gras Omega-3, Obesity, Metabolic syndrome, Steatosis, Lipogenesis, Gluconeogenesis, Insulin resistance, Oxidative stress, Mitochondria dysfunction, Endotoxemia, Treatment, Functional foods, Proteomic profile, Cardiometabolic disorders, Omega-3 Fatty acids