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Cited by 151Treatment of Major DepressionTryptophan and brain disordersNeurotransmitter Receptor Influence on Behavior

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

Open access
Zemdegs, Juliane, Martin, Hugo, Pintana, Hiranya, Bullich, Sebastien, Manta, Stella, Marqués, Marie A., Moro, Cédric, Layé, Sophie +7 more·2019·The Journal of Neuroscience
DOI 10.1523/jneurosci.2904-18.2019PMC PMC6650994
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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. 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.

AI snapshot

Written from the paper’s full text.

TL;DR

In high-fat-diet-fed insulin-resistant male mice, chronic metformin improved peripheral metabolism, lowered circulating branched-chain amino acids (BCAAs), enhanced dorsal raphe serotonin neuron activity and hippocampal serotonin release, and produced anxiolytic/antidepressant-like effects. A half-BCAA diet did not improve glucose metabolism but produced antidepressant-like effects and restored acute fluoxetine response, suggesting BCAAs contribute to the behavioral phenotype.

Key findings

  • HFD-fed mice showed insulin resistance and elevated plasma BCAAs; metformin (300 mg/kg/d for 4 weeks) reduced body weight, fasting glycemia, HOMA-IR, glucose intolerance, and attenuated the BCAA increase (e.g., plasma BCAAs: HFD-Veh vs STD-Veh p=0.0038; HFD-Met vs HFD-Veh p=0.0003).
  • Metformin increased dorsal raphe 5-HT neuron firing rate vs HFD-Veh (p=0.032), increased input resistance and spikes in patch-clamp recordings (p<0.0001), and reversed the blunted phenylephrine response (p=0.0339).
  • Basal ventral hippocampal extracellular 5-HT was decreased in HFD-Veh (p=0.04) and HFD-Met (p=0.03) vs STD-Veh, but acute fluoxetine increased 5-HT overflow in STD-Veh and HFD-Met, not HFD-Veh (p=0.46).
  • Metformin partially reversed HFD-induced anxiety in the elevated plus maze (time p=0.04; entries p=0.09) and novelty suppressed feeding (p=0.015), and reduced tail-suspension immobility (p=0.04); a half-BCAA HFD reduced plasma BCAAs by ~40%, did not improve glucose metabolism, but reduced TST immobility (p=0.021) and restored acute fluoxetine response (p=0.009).

Methods

  • Male C57BL/6J mice (5–7 weeks old) were fed a standard diet, high-fat diet, or half-BCAA HFD for up to 16 weeks; metformin (300 mg/kg/d) or fluoxetine (18 mg/kg/d in Methods; 20 mg/kg in Fig. 6 legend) was given in drinking water for the last 4 weeks.
  • Metabolic measures included intraperitoneal glucose tolerance tests, HOMA-IR, and plasma BCAA assay; central measures included in vivo single-unit recordings of dorsal raphe 5-HT neurons, patch-clamp recordings in Pet1-cre-mCherry mice, and intracerebral microdialysis in the ventral hippocampus.
  • Behavioral testing included open field, elevated plus maze, novelty suppressed feeding, tail suspension test, and splash test; analyses used t tests and one-/two-way ANOVAs with post hoc tests, significance p≤0.05.

Limitations

  • The paper states that clinical and preclinical studies are warranted to evaluate metformin or low-BCAA diet as add-on strategies in depressed patients or models without metabolic comorbidities, and notes that antidepressant efficacy in T2D/IR has had few investigations with no consistent conclusions.
  • The paper acknowledges that metformin may act through additional mechanisms, including brain insulin resistance, anti-inflammatory, and neuroprotective effects, beyond circulating BCAAs.
  • Evident from the text: experiments used only male C57BL/6J mice, so sex and strain generalization is untested; metformin did not reverse the basal hippocampal extracellular 5-HT decrease despite behavioral effects, and some behavioral/metabolic effects were partial or non-significant (e.g., EPM entries p=0.09; insulinemia p=0.13).

Model-written summary. Check it against the paper before relying on it.

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Registry

Crossref · 10.1523/jneurosci.2904-18.2019

Cites

72 of 72 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 61 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    At week 16, HFD-Veh mice had higher body weight than STD controls.

    “Four weeks later (16th week), higher body weight was observed in HFD-Veh relative to control mice fed an STD ( p ϭ 0.0003; Fig. 1 A, B)”
    Quote in the paperNot a substantial claim
  • Findingown data

    High-fat diet caused a greater increase in body weight from week 1 to week 12 than standard diet.

    “Exposure to HFD induced a significantly higher increase in body weight from the 1st to the 12th week than that observed in control mice fed an STD.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Metformin lowered body weight in HFD-fed mice compared with HFD-Veh.

    “whereas HFD-Met mice had lower body weight than HFD-Veh mice ( p ϭ 0.02; Fig. 1 A, B).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In mice fed a standard diet, four weeks of metformin did not change performance in the elevated plus maze, novelty suppressed feeding, or tail suspension test.

    “Similarly, at the behavioral level, no significant differences were detected between STD-Veh and STD-Met mice regarding their performances in the EPM (time: 69 Ϯ 6 vs 67 Ϯ 11 s, p ϭ 0.8; entries in open arms: 7.4 Ϯ 1 vs 7.8 Ϯ 1 s, p ϭ 0.8), the NSF (latency to feed: 163 Ϯ 19 vs 202 Ϯ 46 s, p ϭ 0.5), and the TST (88 Ϯ 6 vs 78 Ϯ 8 s, p ϭ 0.4).”
    Quote in the paperSubstantial claim
  • Findingown data

    Fluoxetine did not reverse the anxiogenic-like EPM responses in HFD-fed mice.

    “but not in HFD-Flx-treated mice ( p ϭ 0.99 and p ϭ 0.99; Fig. 6 B, C).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 30
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Metformin decreased fasting glycemia and HOMA-IR in HFD-fed mice, but its effect on insulinemia was not statistically significant.

    “All of these parameters were decreased in HFD-Met mice compared with HDF-Veh mice, albeit not statistically significant for insulinemia ( p ϭ 0.0001; p ϭ 0.13; p ϭ 0.04; Fig. 1D-F ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mice fed a standard diet, four weeks of metformin did not change final body weight, fasting glycemia, fasting plasma insulin, HOMA-IR, or glucose tolerance.

    “Comparing STD-Veh (n ϭ 9) and STD-Met (n ϭ 8) mice using an unpaired t test, we found no statistical differences between groups on final body weight (31.5 Ϯ 0.5 vs 30.2 Ϯ 0.6 g; p ϭ 0.4), fasting glycemia (122 Ϯ 6 vs 110 Ϯ 4 mg/dl; p ϭ 0.1), fasting plasma insulin (1.3 Ϯ 0.3 vs 0.7 Ϯ 0.1 ng/ml; p ϭ 0.3), HOMA-IR (0.39 Ϯ 0.09 vs 0.19 Ϯ 0.03; p ϭ 0.1), and glucose tolerance (AUC 0 -120 : 565 Ϯ 57 vs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HFD increased fasting glycemia, insulinemia, and HOMA-IR relative to controls.

    “With respect to the other metabolic measures, an HFD increased fasting glycemia ( p ϭ 0.0001), insulinemia ( p ϭ 0.0006), and the HOMA-IR ( p ϭ 0.0004) relative to controls (Fig. 1D-F ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HFD-BCAA+/+ feeding for 16 weeks increased body weight, fasting glycemia, insulinemia, and glucose intolerance compared with standard diet.

    “Exposure to HFD-BCAA ϩ/ϩ for 16 weeks induced a significant increase in body weight, fasting glycemia, and insulinemia ( p ϭ 0.0001; p ϭ 0.04; p ϭ 0.04); and resulted in a significant glucose intolerance ( p ϭ 0.0001) compared with control mice fed an STD (Fig. 7B-G).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Home cage food consumption was higher in HFD-BCAA+/+ and HFD-BCAA+/- mice than STD mice but did not reach statistical significance.

    “whereas food home cage consumption based on caloric value consumed was higher in HFD-BCAA ϩ/ϩ and HFD-BCAA ϩ/Ϫ mice compared with STD mice, but did not reach statistical significance (Fig. 8F ).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    HFD-BCAA+/+ and HFD-BCAA+/- mice had increased latency to feed in the novelty suppressed feeding test compared with STD mice, with similar responses between the two HFD groups.

    “In the NSF, although a significant increase in latency to feed was detected in HFD-BCAA ϩ/ϩ and HFD-BCAA ϩ/Ϫ mice compared with STD mice ( p ϭ 0.0002 and p ϭ 0.0065; Fig. 8D), both groups displayed similar responses in this paradigm ( p ϭ 0.35).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    HFD-Veh mice had increased latency to feed in the novelty suppressed feeding test compared with STD-Veh mice.

    “In the NSF, an increased latency to feed, which can be also used as a readout for anxiety, was detected in HFD-Veh mice ( p ϭ 0.0001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Acute fluoxetine increased extracellular 5-HT over baseline in STD-Veh and HFD-Met mice but not in HFD-Veh mice.

    “we observed that this pharmacological compound significantly increased the percentage of [5-HT]ext over baseline in STD-Veh and HFD-Met mice ( p ϭ 0.013 and p ϭ 0.0011, respectively), but such a response was not apparent in HFD-Veh mice ( p ϭ 0.46; Fig. 5C,D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HFD-BCAA+/- mice showed the same metabolic phenotype as HFD-BCAA+/+ mice, with no differences between them.

    “The same phenotype was observed in HFD-BCAA ϩ/Ϫ mice ( p ϭ 0.0001, p ϭ 0.008, p ϭ 0.04, and p ϭ 0.0001), and no differences between HFD-BCAA ϩ/ϩ and HFD-BCAA ϩ/Ϫ mice ( p ϭ 0.73; p ϭ 063; p ϭ 0.99 and p ϭ 0.91; Fig. 7B-G) were detected”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HFD-BCAA+/+ mice had higher latency of first grooming in the splash test compared with STD mice, while HFD-BCAA+/- mice did not.

    “Finally, we showed a higher latency of first grooming in HFD-BCAA ϩ/ϩ mice ( p ϭ 0.04) but not in HFD-BCAA ϩ/Ϫ mice ( p ϭ 0.61) compared with STD mice in the ST”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HFD-Veh mice displayed glucose intolerance, and metformin reversed this effect.

    “In keeping with the latter observations, HFD-Veh mice displayed glucose intolerance ( p ϭ 0.0002), and this effect was reversed by Met ( p ϭ 0.0002; Fig. 1G,H ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In HFD mice, prolonged metformin improved metabolic parameters and was accompanied by reduced anxiety and despair.

    “the improvement of metabolic parameters induced by prolonged administration of Met in mice fed an HFD were accompanied by a reduction of both anxiety and despair”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HFD-BCAA+/- reduced despair and improved self-care.

    “reduced despair, and improvement of self-care was detected in HFD-BCAA ϩ/Ϫ mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Acute fluoxetine failed to exert an antidepressant-like effect in HFD-BCAA+/+ mice, but a normal response was observed in HFD-BCAA+/- mice.

    “Although acute administration of Flx failed to exert an antidepressant-like effect in HFD-BCAA ϩ/ϩ mice, a normal response was observed in HFD-BCAA ϩ/Ϫ mice.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Tryptophan quantity was equivalent between the standard and high-fat diets.

    “We ensured that tryptophan quantity, the precursor for 5-HT synthesis, was equivalent between STDs and HFDs.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    A HOMA-IR score of at least 2.8 represents an insulin-resistant state.

    “HOMA-IR Ն2.8 represents an insulin resistance state (Matthews et al., 1985).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Matthews et al., 1985

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  • Classified as probably not a substantial claim.

    Study design and conductown data

    Mice were randomly assigned to receive a standard diet, a high-fat diet, or a half-BCAA high-fat diet.

    “After 1 week of acclimatization, mice were randomly assigned to receive free access to a standard diet (STD; STD A04, SAFE), an HFD (D12451, Research Diets) or a half-BCAA-HFD (HFD-BCAA ϩ/Ϫ ; MD.1610 version, ENVIGO) up to 16 weeks (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BCAAs can affect the rate of 5-HT production and thereby lead to anxiodepressive symptoms, as shown in clinical and preclinical studies.

    “Thus, the rate of 5-HT production may be affected by BCAAs, thereby leading to anxiodepressive symptoms, as shown in clinical (Fellendorf et al., 2018) and preclinical studies (Coppola et al., 2013;Scaini et al., 2014;Asor et al., 2015).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Fellendorf et al., 2018

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    • cites Coppola et al., 2013

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    • cites Scaini et al., 2014

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In humans, the severity of insulin resistance is associated with reduced brain volume.

    “In humans, associations between the severity of IR and the reduction of brain volume have been unveiled (Last et al., 2007;Phillips et al., 2018).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Last et al., 2007

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    • cites Phillips et al., 2018

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  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Metformin and fluoxetine concentrations in drinking water were adjusted according to monitored water intake to achieve comparable dosing between STD and HFD mice.

    “Because daily water consumption might have differed between STD and HFD mice, metformin and fluoxetine concentrations in drinking water were adjusted accordingly to achieve comparable dosing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Before treatments began at week 12, the HFD groups were balanced and had similar average individual weights.

    “Before the initiation of the different treatments (12th week), HFD groups of mice were balanced, and the average individual weights were similar (Fig. 1A).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Fluid intake was similar among STD-Veh, HFD-Veh, and HFD-Met mice.

    “During this period, fluid intake was similar among STD-Veh, HFD-Veh, and HFD-Met mice (Fig. 1C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Tryptophan levels are decreased in the CNS of patients with type 2 diabetes and in rodents fed a high-fat diet.

    “Consistent with this hypothesis, decreased levels of tryptophan were detected in the CNS of patients with T2D (Kloiber et al., 2010;Herrera-Marquez et al., 2011) or in rodents fed an HFD (Kim et al., 2013;Derkach et al., 2015).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kloiber et al., 2010

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    • cites Herrera-Marquez et al., 2011

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    • cites Kim et al., 2013

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    Premisecitation

    High-fat diet leads to anhedonia and decreased self-care.

    “The observation that HFD leads to anhedonia and decreased self-care (Dutheil et al., 2016;Zemdegs et al., 2016)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dutheil et al., 2016

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    • cites Zemdegs et al., 2016

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    People with type 2 diabetes and insulin resistance are twice as likely to develop depression compared to people without diabetes.

    “people experiencing type 2 diabetes and IR are twice as likely to develop depression compared to people without diabetes (Anderson et al., 2001;de Groot et al., 2001).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Anderson et al., 2001

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    • cites de Groot et al., 2001

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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    By attenuating circulating BCAA levels, metformin could favor tryptophan availability in the brain and positively affect central 5-HT tone.

    “By attenuating circulating BCAA levels, Met could favor tryptophan availability in the brain and thereby positively reverberate on central 5-HT tone.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Anxiety is a predominant feature of depression and can precede the onset of the pathology.

    “anxiety manifests as a predominant feature of depression and can also precede the onset of the pathology (Malhi and Mann, 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Malhi and Mann, 2018

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  • May combine two claims.

    Premisecitation

    Increased insulin resistance drives higher circulating fasting BCAA levels, and rats fed a diet high in BCAAs display increased rates of insulin resistance.

    “Interestingly, increased IR drives higher circulating fasting BCAA levels (Mahendran et al., 2017), while rats fed a diet high in BCAAs displayed increased rates of IR (Newgard et al., 2009;Zhao et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Mahendran et al., 2017

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    • cites Newgard et al., 2009

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    • cites Zhao et al., 2016

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  • May combine two claims.

    Interpretationown data

    In the CNS, HFD impaired electrical properties of DR 5-HT neurons and 5-HT release, resulting in altered emotionally related behaviors, whereas metformin improved these peripheral and central parameters.

    “In the CNS, HFD impaired both the electrical properties of DR 5-HT neurons and 5-HT release, resulting in altered emotionally related behaviors, whereas Met improved all these peripheral and central parameters.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BCAA supplementation reduced brain 5-HT content in rats and induced depressive-like symptoms such as anxiety or anhedonia in rodents.

    “This is consistent with findings reporting that supplementation in BCAAs reduced brain 5-HT content in rats (Choi et al., 2013) and induced depressive-like symptoms in rodents such as anxiety (Coppola et al., 2013) or anhedonia (Scaini et al., 2014).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Choi et al., 2013

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    • cites Coppola et al., 2013

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    • cites Scaini et al., 2014

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  • May combine two claims.

    Interpretationcitation

    Altered excitability observed in patch-clamp recordings might not affect basal firing rate but could limit DR neuron activation in response to stimuli that increase norepinephrine release, which accelerates pacemaker activity via alpha1 adrenoceptors.

    “It is plausible that the altered excitability observed in patch-clamp recordings would not affect the basal firing rate but would rather limit DR neuron activation in response to diverse stimuli that notably increased norepinephrine release, which is known to accelerate the pacemaker activity of 5-HT neurons in an ␣1 adrenoceptor-dependent manner (Aghajanian, 1985).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aghajanian, 1985

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  • May combine two claims.

    Interpretationown data

    In the HFD model, metformin elicited both anxiolytic- and antidepressant-like responses.

    “In this model, Met elicited both anxiolytic-and antidepressant-like responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    BCAA deficiency might exert antidepressant-like properties while maintaining a high level of anxiety.

    “Together, these results led us to envision that deficiency in BCAA might exert antidepressant-like properties while maintaining a high level of anxiety.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Reducing dietary BCAAs by half lowers brain BCAA levels enough to alter tryptophan uptake and central serotonergic function.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The tail suspension test and forced swim stress were designed to screen antidepressant-like activity rather than to determine depressive-like behavior.

    “the TST and the forced swim stress have been developed to screen antidepressant-like activity rather than to ascertain depressive-like behavior (Nestler and Hyman, 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nestler and Hyman, 2010

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    Interpretationcitation

    Metformin's anxiolytic and antidepressant-like effects could also recruit anti-inflammatory and neuroprotective properties.

    “A possible mechanism underpinning the anxiolytic-and antidepressant-like effects of Met could thus also recruit such properties.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Improvement of brain insulin resistance could represent another mechanism underlying metformin's beneficial action.

    “an improvement of brain IR could represent another mechanism underlying the beneficial action of Met.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The brain has a high density of insulin receptors.

    “the brain is endowed with a high density of insulin receptors (Kleinridders et al., 2014)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kleinridders et al., 2014

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  • May combine two claims.

    Premisecitation

    Different classes of antidiabetic agents or adiponectin produce antidepressant-like activities.

    “different classes of antidiabetic agents or adiponectin, a hormone exerting insulin-sensitizing action, produces antidepressant-like activities (Ho et al., 2012;Liu et al., 2012;Gupta et al., 2014;Su et al., 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ho et al., 2012

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    • cites Liu et al., 2012

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    • cites Gupta et al., 2014

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Combining metformin with an SSRI could be a new potentiation strategy with a wide spectrum of action.

    “the association of this antidiabetic drug with an SSRI could be a new potentiation strategy exerting a wide spectrum of action.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Any increase in 5-HT release at nerve terminals may be counterbalanced by an active 5-HT reuptake process.

  • May combine two claims.

    Premisecitation

    Metformin produces antidepressant-like activities alone or in combination with fluoxetine in chronically stressed animals.

    “Met produces antidepressant-like activities given either alone (Liu et al., 2019) or in combination with Flx (Poggini et al., 2019) in chronically stressed animals.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Liu et al., 2019

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    • cites Poggini et al., 2019

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is a strong correlation between improvement in plasma glycated hemoglobin levels and depression score.

    “unveiling a strong correlation between improvement in plasma glycated hemoglobin levels and depression score (Guo and Lu, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Guo and Lu, 2014

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  • May combine two claims.

    Premisecitation

    Metformin crosses the blood-brain barrier and has anti-inflammatory and neuroprotective effects in the brain.

    “Met crosses the BBB and has several beneficial effects in the brain such as anti-inflammatory and neuroprotective effects (Łabuzek et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Łabuzek et al., 2010

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  • May combine two claims.

    Interpretationown data

    The present study proposes a new antidepressant strategy based on chronic metformin treatment, which acts at least in part by reducing circulating BCAAs and stimulating 5-HT release in the ventral hippocampus.

    “The present study proposes a new antidepressant strategy based on chronic treatment with Met, which acts, at least in part, by reducing circulating levels of BCAAs and by stimulating 5-HT release in the vHP (Fig. 10).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The efficacy of antidepressant drugs in type 2 diabetes and insulin resistance has been investigated in only a few studies, with no consistent conclusions.

    “The efficacy of antidepressant drugs in a context of T2D and IR both in humans and rodents has been subjected to only few investigations, and no consistent conclusions have been provided (Anderson et al., 2010;Bryan et al., 2010;Isingrini et al., 2010;Gois et al., 2014;Zemdegs et al., 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Anderson et al., 2010

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    • cites Bryan et al., 2010

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    • cites Isingrini et al., 2010

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44 of 44

  • The paper relies on this without support.

    Reducing dietary BCAAs by half lowers brain BCAA levels enough to alter tryptophan uptake and central serotonergic function.

    “Because changes in plasma BCAAs are known to limit tryptophan availability into the brain, we also provided evidence that partial deficiency of BCAAs in diet is sufficient to exert antidepressant-like activity.”
    “we designed a modified HFD in which the BCAA dietary supply was reduced by half.”

  • The authors state this as an assumption.

    Any increase in 5-HT release at nerve terminals may be counterbalanced by an active 5-HT reuptake process.

    “we assumed that any increase in 5-HT release at the nerve terminals may be counterbalanced by an active 5-HT reuptake process.”

  • The paper relies on this without support.

    Peripheral insulin resistance is associated with anxiogenic-like response.

    “Peripheral insulin resistance has been associated with anxiogenic-like response, one of the most visible and early symptoms of depression.”

  • The paper relies on this without support.

    Peripheral insulin resistance is responsible for an increase in plasma BCAA levels.

    “This metabolic impairment is also responsible for an increase in plasma BCAA (Val, Leu, Isoleu) levels”

  • The paper relies on this without support.

    BCAAs limit tryptophan availability in DR 5-HT neurons due to lower brain penetration across LAT1 expressed on the BBB.

    “which limit tryptophan availability in DR 5-HT neurons due to a lower brain penetration across LAT1 expressed on the BBB.”

  • The paper relies on this without support.

    Such effects impair DR 5-HT neuronal activity and 5-HT release at nerve terminals, leading to despair.

    “Such effects are believed to impair DR 5-HT neuronal activity and 5-HT release at the nerve terminals, thereby leading to despair, another symptom of depression.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Chronic HFD in male mice, leading to increased anxiety-like behavior, impairs basal electrical activity and excitability of serotonin neurons and serotonin-mediated neurotransmission in the hippocampus.

    “Chronic HFD in male mice, leading to increased anxiety-like behavior, has been shown to impair the basal electrical activity and excitability of serotonin neurons as well as serotonin-mediated neurotransmission in the hippocampus [33,35].”

    From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [35]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Two fluoxetine doses are given for the chronic treatment

    Minor

    The methods specify 18 mg/kg/day of fluoxetine in drinking water, but Figure 6 describes the four-week drinking-water treatment as 20 mg/kg.

1 of 1

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Authors
Zemdegs, J., Martin, H., Pintana, H., Bullich, S., Manta, S., Marqués, M. A., Moro, C., Layé, S., Ducrocq, F., Chattipakorn, N., Chattipakorn, S. C., Rampon, C., Pénicaud, L., Fioramonti, X., & Guiard, B. P.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Université de Bordeaux (FR)
  • Université Toulouse III - Paul Sabatier (FR)
  • Chiang Mai University (TH)
  • Université Paris-Sud (FR)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2019-06-03
Volume
39
Issue
30
Pages
5935-5948
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.2904-18.2019
PMC
PMC6650994
OpenAlex
W2948900739
Semantic Scholar
d9d70824a5eecc67fd01c38316b5fb433a115a19
Cited by
151
References
72
Citations by year
2026: 9 · 2025: 22 · 2024: 17 · 2023: 27 · 2022: 22 · 2021: 30 · 2020: 21 · 2019: 3
FWCI
11.78
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
Funders
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • National Science and Technology Development Agency (RTA6080003)
  • Institut National de la Recherche Agronomique
  • Royal Golden Jubilee (RGJ) Ph.D. Programme
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
metformin, insulin resistance, branched-chain amino acids, depression, anxiety, serotonin, dorsal raphe neurons, hippocampus, tryptophan metabolism, high-fat diet, antidepressant-like effects, fluoxetine, type 2 diabetes, metabolic comorbidities, dietary amino acid restriction, insulin-sensitizing therapy
MeSH terms
Amino Acids, Branched-Chain, Animals, Antidepressive Agents, Anxiety, Depression, Hypoglycemic Agents, Insulin Resistance, Male, Metformin, Mice, Inbred C57BL, Anti-Anxiety Agents, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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