Insulin resistance in humans is associated with increased risk of major depression. Such a relationship has been also found in rodents fed a high-fat diet. To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, Zemdegs and colleagues tested the effects of metformin, an oral antidiabetic drug, in mice fed a high fat diet. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Metformin also increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. A diet poor in branched-chain amino acids produced similar results. The authors suggest that metformin could be used as add-on therapy to conventional antidepressants to relieve depressive symptoms in patients with metabolic comorbidities.

Zemdegs J, Martin H, Pintana H, Bullich S, Manta S, et al.: Metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J. Neurosci. 39(30): 5935-5948 (2019).

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