Date: 15 Apr 2014

Phosphorylation of hypothalamic AMPK on serine485/491 related to sustained weight loss by alpha-lipoic acid in mice treated with olanzapine

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Alpha-lipoic acid (ALA) was shown to suppress atypical antipsychotic drug (AAPD)-induced weight gain. However, its mode of action has remained unidentified.


We aimed to identify mechanisms underlying anti-obesity effects of ALA in mice treated with olanzapine.


We compared body weight and food intake among vehicle-, olanzapine-, and olanzapine plus ALA-treated mice, and measured hypothalamic AMP-activated protein kinase (AMPK) activity by detecting levels of Thr172 and Ser485/491 phosphorylation, which indicate activation and inhibition of AMPK, respectively.


Body weights were increased by olanzapine in parallel with increased levels of Thr172 phosphorylation of hypothalamic AMPK. Initially increased rate of weight gain was diminished as Thr172 phosphorylation levels were decreased to control levels after 10 days of olanzapine treatment. ALA successfully not only prevented olanzapine-induced weight gain but also induced additional weight loss even relative to control levels throughout the treatment period. During the initial stage, ALA’s action was indicated by both suppression of olanzapine-induced Thr172 phosphorylation and an increase in Ser485/491 phosphorylation levels. However, in the later stage when no more increases in Thr172 phosphorylation and weight gain by olanzapine were observed, ALA’s action was only indicated by increased levels of Ser485/491 phosphorylation.


Our data suggest that anti-obesity effects of ALA may be related to modulation of both Ser485/491 phosphorylation and Thr172 phosphorylation of hypothalamic AMPK, while olanzapine-induced weight gain may be only associated with increase in Thr172 phosphorylation. This might be an important mechanistic clue for the future development of anti-obesity drugs beyond control of AAPD-induced weight gain.