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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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Abstract

Rationale

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

Objective

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

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgments

This study was supported by the Choi Shin-Hai Neuropsychiatry Research Fund (2011) from the Korean Neuropsychiatric Research Foundation. We thank Eli-Lilly (Korea) for the generous gift of olanzapine.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Psychiatry, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea

    Hyunjeong Kim, Minsun Park, Su-Kyoung Lee, Jihyeon Jeong, Kee Namkoong, Hyun-Sang Cho, Jin Young Park & Eosu Kim

  2. Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    Minsun Park, Kee Namkoong, Hyun-Sang Cho, Jin Young Park & Eosu Kim

  3. Department of Neurology, Yonsei University College of Medicine, Seoul, Republic of Korea

    Byung-In Lee

  4. Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Republic of Korea

    Hyunjeong Kim, Jihyeon Jeong, Byung-In Lee & Eosu Kim

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  1. Hyunjeong Kim
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  2. Minsun Park
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Correspondence to Eosu Kim.

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Kim, H., Park, M., Lee, SK. et al. Phosphorylation of hypothalamic AMPK on serine485/491 related to sustained weight loss by alpha-lipoic acid in mice treated with olanzapine. Psychopharmacology 231, 4059–4069 (2014). https://doi.org/10.1007/s00213-014-3540-3

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  • DOI: https://doi.org/10.1007/s00213-014-3540-3

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