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

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.

A Novel Gliotransmitter, L-β-Aminoisobutyric Acid, Contributes to Pathophysiology of Clinical Efficacies and Adverse Reactions of Clozapine

“…Chronic administration of therapeutically relevant doses of clozapine, quetiapine, brexpiprazole, and lurasidone decreased IP3 synthesis, and increased AMP levels in the rat hypothalamus [ 46 , 47 , 67 ]. However, contrary to expectations, AMPK signallings were activated and unaffected by high-risk (clozapine and quetiapine) and low-risk (brexpiprazole and lurasidone) antipsychotics for weight gain, respectively [ 44 , 45 , 46 , 47 , 68 ].…”

“…Based on previous clinical and preclinical findings, it is hypothesised that clozapine activates hypothalamic signalling associated with AMPK via enhanced BAIBA signalling. The BAIBA enantiomer activates AMPK signalling in the hypothalamus and astrocytes [ 46 , 47 , 67 ] ( Figure 2 ). According to our hypothesis, chronic administration of therapeutically relevant doses of clozapine increases the synthesis and release of the BAIBA enantiomer, but neither brexpiprazole nor lurasidone affects BAIBA in the hypothalamus [ 46 , 47 , 67 ].…”

“…The BAIBA enantiomer activates AMPK signalling in the hypothalamus and astrocytes [ 46 , 47 , 67 ] ( Figure 2 ). According to our hypothesis, chronic administration of therapeutically relevant doses of clozapine increases the synthesis and release of the BAIBA enantiomer, but neither brexpiprazole nor lurasidone affects BAIBA in the hypothalamus [ 46 , 47 , 67 ]. This effect of clozapine on the BAIBA enantiomer is primarily on L-BAIBA, whereas the D-BAIBA level in the hypothalamus is lower than the limit of detection [ 46 , 47 , 67 ].…”

“…According to our hypothesis, chronic administration of therapeutically relevant doses of clozapine increases the synthesis and release of the BAIBA enantiomer, but neither brexpiprazole nor lurasidone affects BAIBA in the hypothalamus [ 46 , 47 , 67 ]. This effect of clozapine on the BAIBA enantiomer is primarily on L-BAIBA, whereas the D-BAIBA level in the hypothalamus is lower than the limit of detection [ 46 , 47 , 67 ]. Therefore, L-BAIBA is a candidate molecule in the brain contributing to the pathophysiology of clozapine-induced weight gain and metabolic complications.…”

“…Most studies report that D-BAIBA is the main enantiomer of BAIBA in urine [ 132 , 141 , 142 , 143 , 144 ]. Another study suggested L-BAIBA is the major BAIBA enantiomer in the plasma [ 132 ], whereas others have reported that the more prevalent isoform is D-BAIBA [ 46 , 47 , 67 , 144 , 145 ]. Chronic administration of therapeutically relevant doses of clozapine increased L-BAIBA levels but did not affect D-BAIBA levels, resulting in unchanging overall plasma levels of the BAIBA enantiomer [ 46 , 47 , 67 ].…”