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

dc.rights.licenseopenen_US
dc.contributor.authorZEMDEGS, Juliane
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorMARTIN, Hugo
dc.contributor.authorPINTANA, Hiranya
dc.contributor.authorBULLICH, Sebastien
dc.contributor.authorMANTA, Stella
dc.contributor.authorMARQUES, Marie A.
dc.contributor.authorMORO, Cedric
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorLAYE, Sophie
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorDUCROCQ, Fabien
dc.contributor.authorCHATTIPAKORN, Nipon
dc.contributor.authorCHATTIPAKORN, Siriporn C.
dc.contributor.authorRAMPON, Claire
dc.contributor.authorPENICAUD, Luc
hal.structure.identifierNutrition et Neurobiologie intégrée [NutriNeuro]
dc.contributor.authorFIORAMONTI, Xavier
dc.contributor.authorGUIARD, Bruno P.
dc.date.accessioned2021-08-27T07:47:32Z
dc.date.available2021-08-27T07:47:32Z
dc.date.issued2019-06-03
dc.identifier.issn1529-2401en_US
dc.identifier.urioai:crossref.org:10.1523/jneurosci.2904-18.2019
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/110225
dc.description.abstractEnEpidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities. SIGNIFICANCE STATEMENT Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.
dc.language.isoENen_US
dc.sourcecrossref
dc.subject.enBranched-chain amino acids
dc.subject.enDepression
dc.subject.enHippocampusi
dc.subject.enInsulin resistance
dc.subject.enMetformin
dc.subject.enSerotonin
dc.title.enMetformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids
dc.typeArticle de revueen_US
dc.identifier.doi10.1523/jneurosci.2904-18.2019en_US
dc.subject.halSciences du Vivant [q-bio]/Neurosciences [q-bio.NC]en_US
dc.identifier.pubmed31160539en_US
bordeaux.journalJournal of Neuroscienceen_US
bordeaux.page5935-5948en_US
bordeaux.volume39en_US
bordeaux.hal.laboratoriesNutriNeurO (Laboratoire de Nutrition et Neurobiologie Intégrée) - UMR 1286en_US
bordeaux.issue30en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINRAEen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcedissemin
hal.exportfalse
workflow.import.sourcedissemin
dc.rights.ccPas de Licence CCen_US
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