TLR4-dependent neuroinflammation mediates LPS-driven food-reward alterations during high-fat exposure.

Autor: Huwart SJP; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 Box B1.73.11, Brussels, B-1200, Belgium.; Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Avenue Pasteur, 6, Wavre, Belgium., Fayt C; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 Box B1.73.11, Brussels, B-1200, Belgium.; Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Avenue Pasteur, 6, Wavre, Belgium., Gangarossa G; Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, F-75013, France.; Institut Universitaire de France (IUF), Paris, France., Luquet S; Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, F-75013, France., Cani PD; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 Box B1.73.11, Brussels, B-1200, Belgium.; Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Avenue Pasteur, 6, Wavre, Belgium.; Institute of Experimental and Clinical Research (IREC), UCLouvain, Université catholique de Louvain, Brussels, Belgium., Everard A; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Av. E. Mounier, 73 Box B1.73.11, Brussels, B-1200, Belgium. amandine.everard@uclouvain.be.; Walloon Excellence in Life Sciences and BIOtechnology (WELBIO) Department, WEL Research Institute, Avenue Pasteur, 6, Wavre, Belgium. amandine.everard@uclouvain.be.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2024 Nov 23; Vol. 21 (1), pp. 305. Date of Electronic Publication: 2024 Nov 23.
DOI: 10.1186/s12974-024-03297-z
Abstrakt: Background: Obesity has become a global pandemic, marked by significant shifts in both the homeostatic and hedonic/reward aspects of food consumption. While the precise causes are still under investigation, recent studies have identified the role of gut microbes in dysregulating the reward system within the context of obesity. Unravelling these gut-brain connections is crucial for developing effective interventions against eating and metabolic disorders, particularly in the context of obesity. This study explores the causal role of LPS, as a key relay of microbiota component-induced neuroinflammation in the dysregulation of the reward system following exposure to high-fat diet (HFD).
Methods: Through a series of behavioural paradigms related to food-reward events and the use of pharmacological agents targeting the dopamine circuit, we investigated the mechanisms associated with the development of reward dysregulation during HFD-feeding in male mice. A Toll-like receptor 4 (TLR4) full knockout model and intraventricular lipopolysaccharide (LPS) diffusion at low doses, which mimics the obesity-associated neuroinflammatory phenotype, were used to investigate the causal roles of gut microbiota-derived components in neuroinflammation and reward dysregulation.
Results: Our study revealed that short term exposure to HFD (24 h) tended to affect food-seeking behaviour, and this effect became significant after 1 week of HFD. Moreover, we found that deletion of TLR4 induced a partial protection against HFD-induced neuroinflammation and reward dysregulation. Finally, chronic brain diffusion of LPS recapitulated, at least in part, HFD-induced molecular and behavioural dysfunctions within the reward system.
Conclusions: These findings highlight a link between the neuroinflammatory processes triggered by the gut microbiota components LPS and the dysregulation of the reward system during HFD-induced obesity through the TLR4 pathway, thus paving the way for future therapeutic approaches.
Competing Interests: Declarations. Ethical approval: The mouse experiments were approved by the UCLouvain Health Sector’s ethical committee (approval numbers: 2022/UCL/MD/05, 2023/UCL/MD/A5, and 2023/UCL/MD/A12), conducted in accordance with the local ethics committee guidelines and compliant with the Belgian Law of May 29, 2013, concerning the protection of laboratory animals (agreement numbers: LA1230314 and LA2230641). Competing interests: A.E. and P.D.C. are inventors on patent applications dealing with the use of A. muciniphila and its components in the treatment of metabolic disorders. A. E., SJPH and P.D.C. are inventors on patent applications dealing with gut microbes in food reward dysregulations. P.D.C. was cofounder of The Akkermansia company SA and Enterosys. All other authors declare they have no competing interests. The funders had no role: in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
(© 2024. The Author(s).)
Databáze: MEDLINE
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