Metformin ameliorates olanzapine-induced disturbances in POMC neuron number, axonal projection, and hypothalamic leptin resistance
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Antipsychotics have been widely accepted as a treatment ofchoice for psychiatric illnesses such as schizophrenia. Whileatypical antipsychotics such as aripiprazole are not associatedwith obesity and diabetes, olanzapine is still widely used basedon the anticipation that it is more effective in treating severeschizophrenia than aripiprazole, despite its metabolic side effects. To address metabolic problems, metformin is widely prescribed. Hypothalamic proopiomelanocortin (POMC) neurons have beenidentified as the main regulator of metabolism and energy expenditure. Although the relation between POMC neurons andmetabolic disorders is well established, little is known aboutthe effects of olanzapine and metformin on hypothalamic POMCneurons. In the present study, we investigated the effect of olanzapineand metformin on the hypothalamic POMC neurons infemale mice. Olanzapine administration for 5 days significantlydecreased Pomc mRNA expression, POMC neuron numbers,POMC projections, and induced leptin resistance before theonset of obesity. It was also observed that coadministration ofmetformin with olanzapine not only increased POMC neuronnumbers and projections but also improved the leptin responseof POMC neurons in the olanzapine-treated female mice. Thesefindings suggest that olanzapine-induced hypothalamic POMCneuron abnormality and leptin resistance, which can be amelioratedby metformin administration, are the possible causes ofsubsequent hyperphagia.
Abstract
Antipsychotics have been widely accepted as a treatment ofchoice for psychiatric illnesses such as schizophrenia. Whileatypical antipsychotics such as aripiprazole are not associatedwith obesity and diabetes, olanzapine is still widely used basedon the anticipation that it is more effective in treating severeschizophrenia than aripiprazole, despite its metabolic side effects. To address metabolic problems, metformin is widely prescribed. Hypothalamic proopiomelanocortin (POMC) neurons have beenidentified as the main regulator of metabolism and energy expenditure. Although the relation between POMC neurons andmetabolic disorders is well established, little is known aboutthe effects of olanzapine and metformin on hypothalamic POMCneurons. In the present study, we investigated the effect of olanzapineand metformin on the hypothalamic POMC neurons infemale mice. Olanzapine administration for 5 days significantlydecreased Pomc mRNA expression, POMC neuron numbers,POMC projections, and induced leptin resistance before theonset of obesity. It was also observed that coadministration ofmetformin with olanzapine not only increased POMC neuronnumbers and projections but also improved the leptin responseof POMC neurons in the olanzapine-treated female mice. Thesefindings suggest that olanzapine-induced hypothalamic POMCneuron abnormality and leptin resistance, which can be amelioratedby metformin administration, are the possible causes ofsubsequent hyperphagia.
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