Thèse de Célia Fourrier

Bases neurobiologiques des troubles de l’humeur et de la cognition associés à l’obésité : rôle de l’inflammation

Soutenue le 16 décembre 2016

Directrice de thèse : Dr Nathalie Castanon
Equipe : « Nutrition et Psychoneuroimmunologie : Approches expérimentales et cliniques » (Dr Lucile Capuron) Laboratoire : Nutrition et Neurobiologie Intégrée (NutriNeurO)

 Obesity is a metabolic and inflammatory disorder that represents a major risk factor for development of comorbidities such as diabetes. Obese patients also often experience mood and cognitive dysfunctions that represent risk factors for aggravation of obesity and related outcomes. Reducing the development of such alterations may therefore allow improving health and quality of life of obese subjects.

In this context, this thesis aimed to decipher the neurobiological mechanisms underlying such neuropsychiatric alterations, in order to identify new targets for the development of potential preventive and/or therapeutic strategies to reduce these alterations. To do so, rodent models of obesity such as the db/db mice, which display severe obesity associated with classical features of metabolic syndrome, can be particularly useful. Indeed, these mice display anxiety-like behavior and cognitive alterations, together with neurobiological alterations including chronic low-grade neuroinflammation, hippocampal insulin resistance, and impaired neuronal plasticity. We therefore used this model to first target inflammation, in order to assess its involvement in these behavioral alterations, and second to investigate whether a nutritional intervention with n-3 polyunsaturated fatty acids (n-3 PUFAs) and antioxidants, which are well-known to display anti-inflammatory and neuroprotective properties, improves obesity-associated neuropsychiatric alterations.

By highlighting a causal link between brain tumor necrosis factor-α (TNF-α) and anxiety-like behavior, this work points to TNF-α as a promising target for mood improvement in the context of obesity. Conversely, we showed that n-3 PUFAs/antioxidants-induced cognitive improvement rather involves modulation of hippocampal neuronal plasticity, suggesting that other interesting therapeutic targets may still be identified. This work contributes to show that inflammation, and especially TNF-α, could be an important target to develop therapeutic treatments for mood alterations associated with obesity, whereas nutritional interventions with selective nutrients of interest could help preventing associated cognitive alterations.

Liste des publications :

Fourrier C., Castanon N., and Layé S. (2015) Les troubles de l’humeur associés à l’obésité et au diabète de type 2 : rôle de la neuroinflammation. Diabète et Obésité, Volume 10, n°93.

Fourrier C., Castanon N., and Layé S. (2015) Rôle de l’inflammation dans la dépression associée au diabète. Nutritions et Endocrinologie. Volume 13, n°73.

Larrieu T., Hilal M.L., Fourrier C., De Smedt-Peyrusse V., Sans N., Capuron L., and Laye S. (2014). Nutritional omega-3 modulates neuronal morphology in the prefrontal cortex along with depression-related behaviour through corticosterone secretion. Transl Psychiatry 4, e437.

Larrieu, T., Hilal, L.M., Fourrier, C., De Smedt-Peyrusse, V., Sans N., Capuron L., and Laye S. (2013) Étude du rôle des oméga-3 alimentaires dans les troubles de l’humeur : rôle de l’axe du stress. Cahiers de Nutrition et de Diététique 48:S53.