Anhedonia induced by high-fat diet in mice depends on gut microbiota and leptin

ABSTRACT

Objectives: Imbalanced nutrition and obesity are risk factors for depression, a relationship that in rodents can be modeled by depression-like behavior in response to high-fat diet (HFD). In this work, we examined the role of the intestinal microbiota and the adipocytokine leptin as potential mediators of the effects of HFD to induce anhedonia-like behavior and reduce self-care in mice.

Methods: Male mice were fed a control diet or HFD (60 kJ% from fat) for a period of 4 weeks, after which behavioral tests and molecular analyses (gut microbiome composition, intestinal metabolome, fecal fatty acids, plasma hormone levels) were performed. The role of the intestinal microbiota was addressed by selective depletion of gut bacteria with a combination of non-absorbable antibiotics, while the implication of leptin was examined by the use of leptin-deficient ob/ob mice.

Results: Antibiotic treatment reduced the HFD-induced weight gain and adiposity and prevented HFD-induced anhedonia-like behavior and self-care reduction. These effects were associated with a decrease in fecal fatty acids and intestinal microbiota-related metabolites including short-chain fatty acids, glucose and amino acids. Gut microbiota depletion suppressed the HFD-induced rise of plasma leptin, and the circulating leptin levels correlated with the anhedonia-like behavior and reduced self-care caused by HFD. The anhedonic effect of HFD was absent in leptin-deficient ob/ob mice although these animals gained more weight and adiposity in response to HFD than wild-type mice.

Discussion: The results indicate that anhedonia-like behavior induced by HFD in mice depends on the intestinal microbiome and involves leptin as a signaling hormone.

KEYWORDS:

• Depression
• diet
• intestinal microbiota
• obesity
• leptin
• gut hormones
• peptide YY
• depression-like behavior

Acknowledgements

The authors thank Ingrid Liebmann for RNA extraction and her help in tissue extraction and multiplex hormonal assay and Karin Wagner for her help in the PCR. AMH and PH designed the experiments. AMH ran the animal model, the behavioral tests and the PCR and analyzed the pertinent data including those obtained with multiplex immunoassay. KK ran the microbiome analysis, while GM and SPC conducted the metabolomics analysis. GL performed the fatty acid assays. AF and GZ extracted tissues for analysis. AMH and PH wrote the manuscript, and all authors revised the manuscript.

Disclosure Statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by FP7 EU grant 613979 (MyNewGut, www.mynewgut.eu) and the Austrian Science Fund (FWF grants P25912-B23 and W1241-B18).

Notes on contributors

Ahmed M. Hassan

Ahmed M. Hassan is a Postdoctoral Research Associate (M.D., Ph.D.) and Member of the Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre, Medical University of Graz, Austria.

Giulia Mancano

Giulia Mancano is a Postdoctoral Research Associate (Ph.D.), Department of Food and Nutritional Sciences, Institute for Cardiovascular & Metabolic Research, University of Reading, United Kingdom.

Karl Kashofer

Karl Kashofer is a Lecturer (Ph.D.) and Head of the Research Group of Translational Genome Analysis, Diagnostic & Research Institute of Pathology, Diagnostic & Research Center of Molecular Biomedicine, Medical University of Graz, Austria.

Gerhard Liebisch

Gerhard Liebisch is a Lecturer (Ph.D.) and Head of the Research Group of Lipidomics, Institute of Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, Germany.

Aitak Farzi

Aitak Farzi is a Research Associate (M.D., Ph.D.), Resident and Member of the Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre, Medical University of Graz, Austria.

Geraldine Zenz

Geraldine Zenz is a Postdoctoral Research Associate (Ph.D.) and Member of the Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre, Medical University of Graz, Austria.

Sandrine P. Claus

Sandrine P. Claus is an Associate Professor in Integrative Metabolism (Ph.D.) and Principal Investigator, Department of Food and Nutritional Sciences, Institute for Cardiovascular & Metabolic Research, University of Reading, United Kingdom.

Peter Holzer

Peter Holzer is a Professor of Experimental Neurogastroenterology (Ph.D.) and Head of the Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Centre, Medical University of Graz, Austria.