title: High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice.
abstract: The link between type 2 diabetes mellitus (T2DM) and depression is bidirectional. However, the possibility that metabolic disorders may elicit anxiogenic-like/depressive-like symptoms or alter the efficacy of antidepressant drugs remains poorly documented. This study explored the influence of T2DM on emotionality and proposed a therapeutic strategy that might be used in depressed diabetic patients.
  
  
  
  Mice were fed a high-fat diet (HFD) and subjected to a full comprehensive metabolic and behavioural analysis to establish correlations between metabolic and psychiatric disorders. In vivo intra-hippocampal microdialysis was also applied to propose a mechanism underpinning the phenotype of mice fed the HFD. Finally, we tested whether chronic administration of the selective 5-HT reuptake inhibitor escitalopram or HFD withdrawal could reverse HFD-induced metabolic and behavioural anomalies.
  
  
  
  The increased body weight, hyperglycaemia and impaired glucose tolerance in response to HFD were correlated with anxiogenic-like/depressive-like symptoms. Moreover, this phenotype was associated with decreased extracellular 5-HT levels in the hippocampus which may result from increased sensitivity of the dorsal raphe 5-HT1A autoreceptor. Interestingly, the beneficial effect of prolonged administration of escitalopram was abolished in HFD-fed mice. On the contrary, HFD withdrawal completely reversed metabolic impairments and positively changed symptoms of anxiety, although some behavioural anomalies persisted.
  
  
  
  Our data provide clear-cut evidence that both pathologies are finely correlated and associated with impaired 5-HT mediated neurotransmission in the hippocampus. Further experiments are warranted to define the most adequate strategy for the treatment of such co-morbidity.
  
  
  
  This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.
authors.affiliation: Faculté de Pharmacie, Université Paris Sud XI, Châtenay-Malabry, Cedex, France.|Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale (CRCA) UMR5169, Toulouse, France.|UPS CRCA UMR5169, Université de Toulouse, Toulouse, France.|Center des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS 1324 INRA, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Juliane
authors.initials: J
authors.lastname: Zemdegs
authors.affiliation: Faculté de Pharmacie, Université Paris Sud XI, Châtenay-Malabry, Cedex, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Quesseveur
authors.affiliation: Center des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS 1324 INRA, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: David
authors.initials: D
authors.lastname: Jarriault
authors.affiliation: Center des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS 1324 INRA, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Pénicaud
authors.affiliation: Center des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS 1324 INRA, Université de Bourgogne Franche-Comté, Dijon, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Fioramonti
authors.affiliation: Faculté de Pharmacie, Université Paris Sud XI, Châtenay-Malabry, Cedex, France.|Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale (CRCA) UMR5169, Toulouse, France.|UPS CRCA UMR5169, Université de Toulouse, Toulouse, France.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects*; D008297:Male; D008659:Metabolic Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012701:Serotonin / Q000378:metabolism*
chemical_list: D015283:Citalopram; D012701:Serotonin