Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

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.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.

Genetic and pharmacological inactivation of astroglial connexin 43 differentially influences the acute response of antidepressant and anxiolytic drugs

“…As expected, fluoxetine produced a significant increase in hippocampal extracellular 5‐HT levels ([5‐HT]ext) in both WT and Cx43 KD mice. This rise in hippocampal [5‐HT]ext resulting from the local blockade of SERT has been repeatedly reported in mice at the dose range used in this work . Interestingly, the increase in hippocampal [5‐HT]ext was more pronounced in Cx43 KD mice.…”

“…administration of fluoxetine (5 and 18 mg/kg) (Biotrend Chemikalien) or diazepam (0.5 mg/kg) (Biotrend Chemikalien). The choice of the dose for fluoxetine relied on previous experiments showing its in vivo ability to block the serotonin transporter, thereby promoting an increase in the extracellular 5‐HT levels in the hippocampus and to promote acute antidepressant‐like effects . The dose of diazepam was based on its ability to produce acute anxiolytic‐like effects without sedative activity .…”

“…In this test, the latency to first immobility and the total time of immobility were used as an index of depressive‐like behaviour. Indeed, as previously done and validated in our laboratory, immobility time was calculated over a period of 6 minutes. To avoid interpretation biases, the operator in charge of the treatment did not perform the experiments, and the animal identification was made after the tests using ear tags.…”

Metformin Ameliorates Lipopolysaccharide-Induced Depressive-Like Behaviors and Abnormal Glutamatergic Transmission

“…And metformin decreased the immobility time during the forced swimming test (FST) in this rat model of comorbid depression and diabetic [11]. In mice fed with high fat diet (HFD), metformin decreased the immobility time in the tail suspension test (TST) [12]. In mice subjected to chronic social defeat stress (CSDS), metformin treatment rescued the depressive-like behaviors in social interaction behavioral test, sucrose preference test, FST and TST [13].…”

“…And recently, metformin was also found to be effective as an adjunct to antidepressants in nondiabetic major depressive disorder (MDD) patients [10]. Moreover, metformin is also found to ameliorate depressive-like behaviors in rodent models [11][12][13]. In a rat T2DM model induced by streptozotocin and nicotinamide, foot-shocks were administrated to model comorbid depression in diabetic rats.…”