ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2019
Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04930471 (A Multi-center, Prospective, Cohort Study to Elucidate the Effects of Metformin Treatment on Steroid Hormones and Social Behavior. Linking Autistic Behaviorial Symptoms to Changes in Steroid Hormone Availability), which is not on this map. Cited by 56 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Multi-center, Prospective, Cohort Study to Elucidate the Effects of Metformin Treatment on Steroid Hormones and Social Behavior. Linking Autistic Behaviorial Symptoms to Changes in Steroid Hormone Availability
Who cites it
56 citing papers in PubMed, 143 citations in OpenAlex.
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- Metformin Ameliorates Cognitive Deficits and Neuroinflammation in a Mouse Model of Familial Hypercholesterolemia.Neurochemical research · 2026Article
- Metabolic Modulators in Depression: Emerging Molecular Mechanisms and Therapeutic Opportunities.International journal of molecular sciences · 2025Review
- A High-Fat Diet Induces Oxidative Stress in OPA1Antioxidants (Basel, Switzerland) · 2025Article
- Sex differences in cognition, anxiety-phenotype and therapeutic effect of metformin in the aged apoE-TR mice.Biology of sex differences · 2025Article
- Effect of Combined Treatment with Levofloxacin and Metformin on Diabetes-the Diabetes Related Behavioral and Biochemical Alterations.Turkish journal of pharmaceutical sciences · 2025Article
- The role and mechanism of HMGB1-mediated Notch1/Hes-1 pathway in anxiety and depression-like behaviors in mice with chronic rhinosinusitis.Molecular medicine (Cambridge, Mass.) · 2025Article
- U-shaped relationship between triglyceride glucose-body mass index and suicide attempts in Chinese patients with untreated first-episode major depressive disorder.BMC psychiatry · 2024Article
- Effects of a high-fat diet on cognition and brain distribution of intranasal insulin in E3 and E4 male and female mice.Scientific reports · 2024Article
- BCAAs acutely drive glucose dysregulation and insulin resistance: role of AgRP neurons.Nutrition & diabetes · 2024Article
- Insulin modulates emotional behavior through a serotonin-dependent mechanism.Molecular psychiatry · 2024Article
- Neurological and metabolic related pathophysiologies and treatment of comorbid diabetes with depression.CNS neuroscience & therapeutics · 2024Review
- Effects of calorie, protein, and branched chain amino acid restriction on ovarian aging in mice.Reproductive biology · 2024Article
- Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.Nature genetics · 2024Article
- Heterogeneously elevated branched-chain/aromatic amino acids among new-onset type-2 diabetes mellitus patients are potentially skewed diabetes predictors.World journal of diabetes · 2024Article
- Affective and Cognitive Impairments in Rodent Models of Diabetes.Current neuropharmacology · 2024Review
- Hypoglycemia and anxiolysis mediated by levofloxacin treatment in diabetic rats.Journal of diabetes and metabolic disorders · 2023Article
- Targeting BCAA metabolism to potentiate metformin's therapeutic efficacy in the treatment of diabetes in mice.Diabetologia · 2023Article
- Are steroid hormones and autistic traits affected by metformin? First insights from a pilot.Comprehensive psychoneuroendocrinology · 2023Article
Corrections and comments
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Authors and funding
15 authors at 8 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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