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. 2025 Jun 17.
doi: 10.1007/s00213-025-06834-7. Online ahead of print.

Liraglutide improves depressive and cognitive deficits in a high-fat diet rat model of obesity: the role of hippocampal autophagy and the PI3K/Akt/mTOR pathway

Yosra M Magdy  1 , Sherif A Kamar  2   3 , Mohamed Z Habib  4   5 , Hagar Yousry Rady  3   6 , Mohammed R Rabei  7 , Sara Khedr  1
Affiliations

Liraglutide improves depressive and cognitive deficits in a high-fat diet rat model of obesity: the role of hippocampal autophagy and the PI3K/Akt/mTOR pathway

Yosra M Magdy et al. Psychopharmacology (Berl). .

Abstract

Rationale: Psychiatric disorders are a largely elusive aspect of obesity, representing a growing public health concern. In this regard, a large body of evidence indicates a pivotal role of disturbed autophagic flux in the pathogenesis of obesity-associated neuropsychiatric deficits.

Objectives: This work was designed to evaluate the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, which is increasingly utilized for the management of chronic obesity, on the depressive/cognitive deficits in the high-fat diet (HFD) rat model of obesity with an emphasis on its hippocampal mechanistic backgrounds.

Methods: The effects of chronic liraglutide administration (subcutaneous; 300 µg/kg/day for 28 days) were investigated on depressive-like phenotypes, cognitive deficits, and hippocampal phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR)-regulated autophagy.

Results: Chronic liraglutide treatment amended the HFD-induced depressive-like phenotype (in the sucrose preference and the forced swimming tests) and cognitive deficits (in the Morris water maze test). Moreover, liraglutide enhanced the hippocampal expression of brain-derived neurotrophic factor (BDNF), PI3K, Akt, p-Akt, and p-mTOR and downregulated the expression of the autophagic markers (Beclin-1, LC3) and the inflammatory markers (TNF-α, IL-6) with amelioration of HFD-induced hippocampal neurodegeneration.

Conclusions: This work highlights the antidepressant and pro-cognitive properties of liraglutide in HFD-exposed rats, which could be mediated through amelioration of the disrupted PI3K/Akt/mTOR signaling activity with a possible impedance of the exaggerated autophagy-mediated neurodegenerative cascades. Indeed, this study highlights that liraglutide is not only effective in weight control, but its effects also extend to managing obesity-related psychiatric disorders.

Keywords: Autophagy; Cognitive dysfunction; Depression; High-fat diet; Hippocampus; Liraglutide.

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Conflict of interest statement

Declarations. Ethical approval: The study was conducted in accordance with EU Directive 2010/63/EU for animal experiments and was approved by the Research Ethics Committee of the Faculty of Medicine, Ain Shams University (FMASU-REC). FMASU-REC operates under Federal Wide Assurance. No. FWA 000017585 (approval number: FMASU R231/2022). Consent to participate: Not applicable. Consent to publish: Not applicable. Competing interests: On behalf of all authors, the corresponding author states that there is no conflict of interest. Conflict of interest: All authors declared that there is no conflict of interest.

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