From gut to brain Exploring mechanisms and therapeutic targets of obesity

In this thesis, we aim to deepen our understanding of the pathogenesis and consequences of obesity, which is essential for developing novel strategies for both prevention and treatment.
Part I emphasizes the importance of recognizing obesity and its implications during illnesses, such as COVID-19. Part II investigates the role of the gut and its interactions with the brain and metabolic health. In Chapter 3, we provide a comprehensive literature review on the gut microbiota and its interaction with the brain in the context of obesity. In Chapter 4, we demonstrate that the metabolite imidazole propionate is positively correlated with blood pressure. Part III delves into the relationship between autophagy and insulin sensitivity in obesity. Chapter 5 shows that there is no significant correlation between insulin sensitivity and the expression of autophagy-related genes and proteins in adipose tissue. Part IV focuses on the brain in obesity. Chapter 6 shows that individuals with obesity experience increased food craving, though no correlation was found between food craving and striatal dopamine transporter availability. Chapter 7 demonstrates that the dopamine receptor agonist bromocriptine significantly reduces fasting glucose levels in patients with type 2 diabetes, but without improving peripheral or hepatic insulin sensitivity. Furthermore, there was no observed dexamphetamine-induced striatal dopamine release either at baseline or post-intervention, suggesting reduced brain dopaminergic responsivity in obesity.
In conclusion, this thesis addresses several mechanistic aspects and medical consequences of obesity in humans, underscoring the importance of recognizing obesity as a complex and multifaceted disease.