Branched-chain amino acids are associated with metabolic parameters in bipolar disorder

Fellendorf, Frederike T.; Platzer, Martina; Pilz, René; Rieger, Alexandra; Kapfhammer, Hans-Peter; Mangge, Harald; Dalkner, Nina; Zelzer, Sieglinde; Meinitzer, Andreas; Birner, Armin; Bengesser, Susanne; Queissner, Robert; Hamm, Carlo; Hartleb, Riccarda; Reininghaus, Eva

doi:10.1080/15622975.2018.1487077

Cited by 19 publications

(7 citation statements)

References 23 publications

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“…Indeed, elevated circulating BCAA levels predict the severity of IR (Newgard et al, 2009;Gannon et al, 2018) while limiting the uptake of tryptophan into the brain through the blood-brain barrier (BBB) by the large neutral amino acid transporter 1 (LAT1; Pardridge, 1998). 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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Dalkner et al also observed increased fat craving in males vs. females with BD (43). In line with this, Fellendorf et al found a decrease of the branched chain amino acid leucine in BD compared to controls and associations between leucine, valine, isoleucine, and anthropometric as well as glucose metabolism in the BD cohort (68).…”

Section: Introductionmentioning

confidence: 75%

Weight Gain During Treatment of Bipolar Disorder (BD)—Facts and Therapeutic Options

et al. 2019

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Bipolar disorder (BPD) is a mood disorder, which is characterized by alternating affective states, namely (hypo)mania, depression, and euthymia. Evidence is growing that BPD has indeed a biologic substrate characterized by chronic inflammation, oxidative stress, and disturbed energy metabolism. Apart from this, there is obviously a hereditary component of this disease with multi-genetic factors. Most probably a susceptibility threshold favors the outbreak of clinical disease after a cascade of stress events that remain to be elucidated in more detail. Evidence is also growing that weak points in brain energy metabolism contribute to outbreak and severity of BPD. Conventional psychopharmacologic therapy must be reassessed under the aspects of weight cycling and development of central obesity as a deterioration factor for a worse clinical course leading to early cardiovascular events in BPD subgroups.

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“…BCAA metabolism contributes to the synthesis of new glutamate when this amino acid becomes depleted in the neurons in response to oxidative stress, and therefore, this process plays a crucial role in brain function homeostasis [ 75 ]. The levels of BCAA, leucine, isoleucine, and Val are decreased in patients suffering from psychiatric disorders such as major depressive disorder, immune-related major depression, and bipolar disorder [ 76 , 77 , 78 ]. BCAA levels are also elevated in the hippocampus after antidepressant treatment [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic and Transcriptomic Signatures of the Acute Psychological Stress Response in the Mouse Brain

2023

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Acute stress response triggers various physiological responses such as energy mobilization to meet metabolic demands. However, the underlying molecular changes in the brain remain largely obscure. Here, we used a brief water avoidance stress (WAS) to elicit an acute stress response in mice. By employing RNA-sequencing and metabolomics profiling, we investigated the acute stress-induced molecular changes in the mouse whole brain. The aberrant expression of 60 genes was detected in the brain tissues of WAS-exposed mice. Functional analyses showed that the aberrantly expressed genes were enriched in various processes such as superoxide metabolism. In our global metabolomic profiling, a total of 43 brain metabolites were significantly altered by acute WAS. Metabolic pathways upregulated from WAS-exposed brain tissues relative to control samples included lipolysis, eicosanoid biosynthesis, and endocannabinoid synthesis. Acute WAS also elevated the levels of branched-chain amino acids, 5-aminovalerates, 4-hydroxy-nonenal-glutathione as well as mannose, suggesting complex metabolic changes in the brain. The observed molecular events in the present study provide a valuable resource that can help us better understand how acute psychological stress impacts neural functions.

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Branched-chain amino acids are associated with metabolic parameters in bipolar disorder

Cited by 19 publications

References 23 publications

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

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

Weight Gain During Treatment of Bipolar Disorder (BD)—Facts and Therapeutic Options

Metabolic and Transcriptomic Signatures of the Acute Psychological Stress Response in the Mouse Brain

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