High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice
British Journal of Pharmacology. 2015-12-09; 173(13): 2095-2110
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BACKGROUND AND PURPOSE: 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.
EXPERIMENTAL APPROACH: 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.
KEY RESULTS: 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.
CONCLUSIONS AND IMPLICATIONS: 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.
LINKED ARTICLES: 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
© 2015 The British Pharmacological Society.