High‐fat diet‐induced metabolic disorders impairs 5‐HT function and anxiety‐like behavior in mice

Abstract

BACKGROUND AND PURPOSEThe 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 APPROACHMice 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 RESULTSThe increased body weight, hyperglycaemia and impaired glucose tolerance in response to HFD were correlated with anxiogeniclike/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-HT 1A 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 IMPLICATIONSOur 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

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

“…Consistent with this hypothesis, decreased levels of tryptophan were detected in the CNS of patients with T2D (Kloiber et al, 2010;Herrera-Marquez et al, 2011) or in rodents fed an HFD (Kim et al, 2013;Derkach et al, 2015). Using intracerebral microdialysis, we showed that mice fed an HFD displayed lower basal hippocampal extracellular 5-HT concentrations (Zemdegs et al, 2016). Exaggerated stimulation of the monoamine oxidase activity-the enzyme responsible for 5-HT degradation-or the indoleamine 2,3-dioxygenase-the enzyme that metabolizes tryptophan along the kynurenine pathway-are putative explanations for such neurochemical changes Dinel et al, 2014;Gupta et al, 2014).…”

“…Evidence also suggests the existence of a positive correlation between IR and major depression (Rasgon and Kenna, 2005). Indeed, the induction of IR in rats or mice, using prolonged exposure to high-fat diet (HFD), causes some hallmark symptoms of depression including anxiety, anhedonia, and despair (Miyata et al, 2004;Ho et al, 2012;André et al, 2014;Gupta et al, 2014;Dutheil et al, 2016;Yang et al, 2016;Zemdegs et al, 2016;Hassan et al, 2018) and exacerbates behavioral abnormalities observed in animal models of depression (Abildgaard et al, 2011;Liu et al, 2014).…”

Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake

“…Information on the mechanisms underlying HFD-induced serotonergic dyshomeostasis and how it translates to an altered mood response is limited. Recently, the anxiogenic/depressive-like phenotype of mice fed a HFD was attributed to an increased sensitivity of the dorsal raphe 5-HT 1A autoreceptor and subsequent reduction in hippocampal 5-HT level [103]. Additionally, the involvement of HFD-induced neuroinflammatory changes in brain regions associated with mood regulation, such as hippocampus has been reported [104].…”

Incubation temperature influences the behavioral traits of a young precocial bird

“…Because we measured multiple behavioral parameters on each individual duckling, we condensed these non‐independent measures from all trials into two values for each individual using a z ‐score analysis, as described in Guilloux, Seney, Edgar, and Sibille () and Labots, Laarakker, Schetters, Arndt, and van Lith (). This statistical technique has been used in studies to measure emotionality in mice from multiple trials (e.g., Mendez‐David et al., ; Piantadosi et al., ; Shepard et al., ; Zemdegs et al., ). It is an improved way to quantify behavior when using multiple trials because it reduces variance and increases reliability of behavioral measures, compared to using the raw behavioral data (Guilloux et al., ).…”