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High-fat diet induces depression-like behaviour in mice associated with changes in microbiome, neuropeptide Y, and brain metabolome
Open accessAbstract
Objectives: The biological mechanisms linking diet-related obesity and depression remain unclear. Therefore, we examined the impact of high-fat diet (HFD) on murine behaviour, intestinal microbiome, brain metabolome, neuropeptide Y (NPY) expression, and dipeptidyl peptidase-4 (DPP-4) activity.Methods: Male C57Bl/6J mice were fed an HFD (60 kJ% from fat) or control diet (12 kJ% from fat) for 8 weeks, followed by behavioural phenotyping. Caecal microbiome was analysed by 16S rDNA sequencing, brain metabolome by 1H nuclear magnetic resonance, NPY expression by PCR and immunoassay, and dipeptidyl peptidase-4 (DPP-4) activity by enzymatic assay. The effect of a 4-week treatment with imipramine (7 mg/kg/day) and the DPP-4 inhibitor sitagliptin (50 mg/kg/day) on HFD-induced behavioural changes was also tested.Results: HFD led to a depression-like phenotype as revealed by reduced sociability and sucrose preference. In the caecum, HFD diminished the relative abundance of Bacteroidetes and increased the relative abundance of Firmicutes and Cyanobacteria. In the brain, HFD modified the metabolome of prefrontal cortex and striatum, changing the relative concentrations of molecules involved in energy metabolism (e.g. lactate) and neuronal signalling (e.g. γ-aminobutyric acid). The expression of NPY in hypothalamus and hippocampus was decreased by HFD, whereas plasma NPY and DPP-4-like activity were increased. The HFD-induced anhedonia remained unaltered by imipramine and sitagliptin.Discussion: The depression-like behaviour induced by prolonged HFD in mice is associated with distinct alterations of intestinal microbiome, brain metabolome, NPY system, and DPP-4-like activity. Importantly, the HFD-evoked behavioural disturbance remains unaltered by DPP-4 inhibition and antidepressant treatment with imipramine.
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Metadata
- Authors
- Hassan, A. M., Mancano, G., Kashofer, K., Fröhlich, E. E., Matak, A., Mayerhofer, R., Reichmann, F., Olivares, M., Neyrinck, A. M., Delzenne, N. M., Claus, S. P., & Holzer, P.
- Affiliations
- Medical University of Graz (AT)
- University of Reading (GB)
- University of Graz (AT)
- UCLouvain (BE)
- Corresponding author
- Holzer, Peter
- ORCID
- Venue
- Nutritional Neuroscience
- Publisher
- Informa UK Limited
- Published
- 2018-04-26
- Volume
- 22
- Issue
- 12
- Pages
- 877-893
- ISSN
- 1028-415X (ISSN-L)
- 1476-8305
- OpenAlex
- W2800089222
- Cited by
- 166
- References
- 62
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 22 · 2023: 17 · 2022: 26 · 2021: 34 · 2020: 23 · 2019: 12 · 2018: 7
- FWCI
- 6.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nutritional Neuroscience (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- Funders
- EU (613979)
- Austrian Science Fund
- FWF (P25912-B23, W1241-B18)
- European Commission
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- high-fat diet, depression-like behavior, obesity, gut microbiota, neuropeptide Y, dipeptidyl peptidase IV, brain metabolome, anhedonia, sociability, sucrose preference, imipramine, sitagliptin, prefrontal cortex, striatum, Bacteroidetes, Firmicutes, GABA, energy metabolism
- MeSH terms
- Gastrointestinal Microbiome, Animals, Behavior, Animal, Brain, Corpus Striatum, Depression, Male, Mice, Inbred C57BL, Neuropeptide Y, Weight Gain, Gene Expression, Prefrontal Cortex, Mice, Metabolome, Diet, High-Fat
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