Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids

Juliane Zemdegs, Hugo Martin, Hiranya Pintana, Sebastien Bullich, Stella Manta, Marie A. Marqués, Cédric Moro, Sophie Layé, Fabien Ducrocq, Nipon Chattipakorn, Siriporn C. Chattipakorn, Claire Rampon, Luc Pénicaud, Xavier Fioramonti, Bruno P. Guiard
J. Neurosci.. 2019-06-03; 39(30): 5935-5948
DOI: 10.1523/jneurosci.2904-18.2019

PubMed
Lire sur PubMed



Zemdegs J(1), Martin H(2), Pintana H(1)(3), Bullich S(1), Manta S(1), Marqués MA(4), Moro C(4), Layé S(2), Ducrocq F(2), Chattipakorn N(3), Chattipakorn SC(3), Rampon C(1), Pénicaud L(5), Fioramonti X(2), Guiard BP(6)(7).

Author information:
(1)Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, 31000 Toulouse, France.
(2)Université de Bordeaux, Institut National de la Recherche Agronomique, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France.
(3)Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
(4)INSERM, Paul Sabatier University, UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Obesity Research Laboratory, 31000 Toulouse, France.
(5)UMR STROMALab, Université de Toulouse, CNRS ERL5311, École Française du Sang, Institut National Polytechnique-École Nationale Vétérinaire de Toulouse, INSERM U1031, BP 84225, F-31432, 31000 Toulouse Cedex 4, France, and.
(6)Centre de Recherches sur la Cognition Animale, Centre de Biologie Intégrative, Université de Toulouse, CNRS, 31000 Toulouse, France, .
(7)Faculté de Pharmacie, Université Paris Sud, Université Paris-Saclay, 92290 Chatenay-Malabry, France.

Epidemiological 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.

Copyright © 2019 the authors.

DOI: 10.1523/JNEUROSCI.2904-18.2019
PMCID: PMC6650994 [Available on 2020-01-24]
PMID: 31160539

Auteurs Bordeaux Neurocampus