Inès Delgado PhD

Abstract

Neuropsychiatric symptoms, notably as they relate to mood, are frequent in obese subjects. Inflammation is believed to contribute to this effect. Obesogenic dietary patterns are not only an essential risk factor for obesity, but they also harbor a pro-inflammatory potential that may set the stage for the development of neuropsychiatric symptoms. They could thus contribute to an increased neuropsychiatric vulnerability when subjects are submitted to conditions that can promote mood symptoms. Nevertheless, being vulnerable may not be sufficient, and some mechanistic pathways need to be involved/activated to precipitate vulnerable individuals into clinically relevant neuropsychiatric states. In this context, tryptophan (TRP), which is at the interface of diet, inflammation, and mood, presents as a good candidate. In support of this notion, inflammation has a strong influence on TRP metabolism, and there is mounting evidence for the role of inflammation-related alterations in TRP metabolism in the pathophysiology of depression in subjects with high levels of inflammation.

This thesis aimed to evaluate the relationship between systemic inflammation, alterations in tryptophan metabolism, and neuropsychiatric symptoms in subjects with obesity and determine whether dietary habits with high obesogenic and inflammatory potential may prime healthy subjects to neuropsychiatric alterations. 

Chapter 1 aimed to characterize neuropsychiatric symptoms in obesity and determine the influence of inflammation and obesogenic dietary habits on this association. Results indicate that obesity is characterized by an increased prevalence of inter-related neuropsychiatric symptoms and low-grade systemic inflammation augmenting with adiposity. Moreover, they support the notion that obesity-related chronic low-grade inflammation contributes to neuropsychiatric symptoms and comorbidity. Finally, they reveal that obesogenic dietary habits promote the development of systemic inflammation and modulate stress-induced cognitive alterations before the instauration of obesity.

Chapter 2 aimed to investigate pathways of TRP metabolism in obese subjects and non-obese subjects with obesogenic dietary habits and assess their association with systemic inflammation. Results indicate that the different pathways of TRP metabolism are altered in obesity, particularly in the form of high kynurenine (KYN)/TRP ratio and low serotonin and indoles levels, compared to non-obese controls. Alterations in the KYN and indole pathways of TRP metabolism were associated with obesity-related systemic inflammation. In contrast, TRP metabolism in the indole pathway appeared to be impacted before the onset of obesity, as the adherence to an obesogenic dietary pattern was sufficient to decrease levels of indole metabolites.

Chapter 3 aimed to evaluate the relevance of alterations in both KYN and indole pathways of TRP metabolism in neuropsychiatric symptoms in obesity, focusing on subsyndromal depression. Results show that inflammation-related changes in TRP metabolism, notably characterized by an increased neurotoxic output of the KYN pathway and low indole-3-carboxaldehyde levels, are associated with subsyndromal depressive symptoms in obese subjects.

These results open different avenues of research and provide support for the development of personalized prevention and treatment strategies of depression based on the clinical, dietary, and biological profiles of patients.

Keywords: neuropsychiatric symptoms; inflammation; obesogenic diet; tryptophan metabolism; obesity

Jury