A Candidate Gliotransmitter, L-β-Aminoisobutyrate, Contributes to Weight Gain and Metabolic Complication Induced by Atypical Antipsychotics

Nutrients · 3 authors, 1 centre

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TL;DR

This preclinical study investigates how the astroglial-derived molecule L-BAIBA contributes to metabolic side effects from atypical antipsychotics. It found that the high-weight-gain drug quetiapine increases L-BAIBA synthesis and activates hypothalamic AMPK signaling, while the low-weight-gain drug lurasidone suppresses L-BAIBA synthesis.

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This preclinical study proposes L-β-aminoisobutyrate (L-BAIBA) as a candidate gliotransmitter mediating antipsychotic-induced metabolic complications. Using animal models, the authors show L-BAIBA is selectively released through activated astroglial hemichannels. Central to the hypothesis, the high-weight-gain antipsychotic quetiapine was found to activate AMPK signaling in both the hypothalamus and astrocytes by increasing L-BAIBA synthesis. Conversely, the lower-risk antipsychotic lurasidone suppressed L-BAIBA synthesis, potentially via 5-HT7 receptor inhibition. The study also notes L-BAIBA release is linked to neural ripple-burst activity, suggesting a role in cognition.

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other

SPECIALTY

psychiatry

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AI pipeline

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ORIGINAL PAPER

PMC10097171

A Candidate Gliotransmitter, L-β-Aminoisobutyrate, Contributes to Weight Gain and Metabolic Complication Induced by Atypical Antipsychotics

Nutrients

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ABSTRACT

Abstract Lurasidone and quetiapine are effective atypical mood-stabilizing antipsychotics, but lurasidone and quetiapine are listed as lower-risk and high-risk for weight gain/metabolic complications, respectively. The pathophysiology of the discrepancy of metabolic adverse reactions between these antipsychotics remains to be clarified. The GABA isomer, β-aminoisobutyric acid (BAIBA) enantiomer, was recently re-discovered as myokine via an AMP-activated protein kinase activator (AMPK) enhancer and inhibitory gliotransmitter. Notably, activation of AMPK in peripheral organs improves, but in the hypothalamus, it aggravates metabolic disturbances. Therefore, we determined effects of chronic administration of lurasidone and quetiapine on intracellular and extracellular levels of the BAIBA enantiomer. L-BAIBA is a major BAIBA enantiomer in the hypothalamus and astrocytes, whereas L-BAIBA only accounted for about 5% of total plasma BAIBA enantiomers. Chronic lurasidone administration did not affect body weight but decreased the L-BAIBA level in hypothalamus and cultured astrocytes, whereas chronic quetiapine administration increased body weight and the L-BAIBA level in hypothalamus and astrocytes. Contrary, neither lurasidone nor quetiapine affected total plasma levels of the BAIBA enantiomer since D-BAIBA levels were not affected by these antipsychotics. These results suggest that activation of intracellular L-BAIBA signaling is, at least partially, involved in the pathophysiology of metabolic adverse reaction of quetiapine. Furthermore, this study also demonstrated that lurasidone and quetiapine suppressed and enhanced astroglial L-BAIBA release induced by ripple-burst stimulation (which physiologically contributes to cognitive memory integration during sleep), respectively. Therefore, L-BAIBA probably contributes to the pathophysiology of not only metabolic adverse reactions, but also a part of clinical action of lurasidone or quetiapine. Keywords: β-aminoisobutyric acid, lurasidone, quetiapine weight gain, AMPK

CITATION EXPORT

Kouji Fukuyama, Eishi Motomura, Motohiro Okada. A Candidate Gliotransmitter, L-β-Aminoisobutyrate, Contributes to Weight Gain and Metabolic Complication Induced by Atypical Antipsychotics. Nutrients. (2023). https://doi.org/10.3390/nu15071621

AUTHORS

3 · 1 CENTRES

Kouji Fukuyama, Eishi Motomura, Motohiro Okada

1Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan