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Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids
Open accessAbstract
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.
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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).
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59 Own result · 32 Not checked yet · 17 Own interpretation · 10 Own method
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“whereas HFD-Met mice had lower body weight than HFD-Veh mice ( p ϭ 0.02; Fig. 1 A, B).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin does not modify glucose metabolism and emotionally related behaviors in mice fed an STD
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“but not in HFD-Flx-treated mice ( p ϭ 0.99 and p ϭ 0.99; Fig. 6 B, C).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“we found decreased input resistance in these neurons in HFD-Veh mice compared with STD-Veh mice without modification of the number of spikes evoked by depolarizing currents ( p Ͻ 0.0001; Fig. 4B-D).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The antidepressant-like effect of Flx was fully restored in HFD-BCAA ϩ/Ϫ mice ( p ϭ 0.009; Fig. 9).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, although the firing rate of DR 5-HT neurons was not modified in HFD-Veh mice compared with STD-Veh mice”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, the frequency and amplitude of sEPSCs or sIPSCs in 5-HT neurons was not affected by HFD feeding ( p ϭ 0.7106 and p ϭ 0.2220 for sEPSCs, respectively; p ϭ 0.9588 and p ϭ 0.4888 for sIPSCs, respectively; Fig. 4 H, I ).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In the EPM, HFD-Veh mice displayed decreased time ( p ϭ 0.0045) and entries in open arms ( p ϭ 0.0002) compared with STD-Veh mice.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 30
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In the paper
“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 ).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin does not modify glucose metabolism and emotionally related behaviors in mice fed an STD
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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 ).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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 ).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
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It may state two separate claims as one.
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In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
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In the paper
“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”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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 ).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
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In the paper
“reduced despair, and improvement of self-care was detected in HFD-BCAA ϩ/Ϫ mice.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
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In the paper
“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.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
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In the paper
“We ensured that tryptophan quantity, the precursor for 5-HT synthesis, was equivalent between STDs and HFDs.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Animals, diets, and drugs.
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In the paper
“HOMA-IR Ն2.8 represents an insulin resistance state (Matthews et al., 1985).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Animals, diets, and drugs.
What the sources say
- Not checked yetcites Matthews et al., 1985
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Animals, diets, and drugs.
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Introduction
What the sources say
- Not checked yetcites Fellendorf et al., 2018
- Not checked yetcites Coppola et al., 2013
- Not checked yetcites Scaini et al., 2014
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Introduction
What the sources say
- Not checked yetcites Last et al., 2007
- Not checked yetcites Phillips et al., 2018
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Animals, diets, and drugs.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Before the initiation of the different treatments (12th week), HFD groups of mice were balanced, and the average individual weights were similar (Fig. 1A).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“During this period, fluid intake was similar among STD-Veh, HFD-Veh, and HFD-Met mice (Fig. 1C).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Introduction
What the sources say
- Not checked yetcites Kloiber et al., 2010
- Not checked yetcites Herrera-Marquez et al., 2011
- Not checked yetcites Kim et al., 2013
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The observation that HFD leads to anhedonia and decreased self-care (Dutheil et al., 2016;Zemdegs et al., 2016)”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Dutheil et al., 2016
- Not checked yetcites Zemdegs et al., 2016
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Anderson et al., 2001
- Not checked yetcites de Groot et al., 2001
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By attenuating circulating BCAA levels, Met could favor tryptophan availability in the brain and thereby positively reverberate on central 5-HT tone.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“anxiety manifests as a predominant feature of depression and can also precede the onset of the pathology (Malhi and Mann, 2018).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Malhi and Mann, 2018
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Mahendran et al., 2017
- Not checked yetcites Newgard et al., 2009
- Not checked yetcites Zhao et al., 2016
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Choi et al., 2013
- Not checked yetcites Coppola et al., 2013
- Not checked yetcites Scaini et al., 2014
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Aghajanian, 1985
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this model, Met elicited both anxiolytic-and antidepressant-like responses.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results led us to envision that deficiency in BCAA might exert antidepressant-like properties while maintaining a high level of anxiety.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Metformin improves glucose metabolism in mice fed an HFD
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Reducing dietary BCAAs by half lowers brain BCAA levels enough to alter tryptophan uptake and central serotonergic function.
In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Nestler and Hyman, 2010
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A possible mechanism underpinning the anxiolytic-and antidepressant-like effects of Met could thus also recruit such properties.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“an improvement of brain IR could represent another mechanism underlying the beneficial action of Met.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the brain is endowed with a high density of insulin receptors (Kleinridders et al., 2014)”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Kleinridders et al., 2014
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Ho et al., 2012
- Not checked yetcites Liu et al., 2012
- Not checked yetcites Gupta et al., 2014
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the association of this antidiabetic drug with an SSRI could be a new potentiation strategy exerting a wide spectrum of action.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Liu et al., 2019
- Not checked yetcites Poggini et al., 2019
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“unveiling a strong correlation between improvement in plasma glycated hemoglobin levels and depression score (Guo and Lu, 2014).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Guo and Lu, 2014
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Met crosses the BBB and has several beneficial effects in the brain such as anti-inflammatory and neuroprotective effects (Łabuzek et al., 2010).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Łabuzek et al., 2010
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
What the sources say
- Not checked yetcites Anderson et al., 2010
- Not checked yetcites Bryan et al., 2010
- Not checked yetcites Isingrini et al., 2010
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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.”
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?
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Animals, diets, and drugs.
“the selective serotonin reuptake inhibitor (SSRI) fluoxetine (Flx) at a dose of 18 mg/kg/d (Biotrend Chemikalien).Both drugs were dissolved and given in the drinking water.”
§ Behavioral/Cognitive Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids > Discussion
“Three groups of mice were fed an HFD and administered Met (300 mg/kg), or Flx (20 mg/kg) or its Veh in the drinking water for 4 weeks.”
Citations
Cites
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“8 represents an insulin resistance state (Matthews et al., 1985).”
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“These data mirror the clinical observations that 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).”
Clinical pharmacokinetics of metformin
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Metadata
- 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
- 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
- bronze
- doi.org
- 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 (medical) › 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
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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.
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