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 Thr(172) and Ser(485/491) phosphorylation, which indicate activation and inhibition of AMPK, respectively. RESULTS: Body weights were increased by olanzapine in parallel with increased levels of Thr(172) phosphorylation of hypothalamic AMPK. Initially increased rate of weight gain was diminished as Thr(172) 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 Thr(172) phosphorylation and an increase in Ser(485/491) phosphorylation levels. However, in the later stage when no more increases in Thr(172) phosphorylation and weight gain by olanzapine were observed, ALA's action was only indicated by increased levels of Ser(485/491) phosphorylation. CONCLUSIONS: Our data suggest that anti-obesity effects of ALA may be related to modulation of both Ser(485/491) phosphorylation and Thr(172) phosphorylation of hypothalamic AMPK, while olanzapine-induced weight gain may be only associated with increase in Thr(172) phosphorylation. This might be an important mechanistic clue for the future development of anti-obesity drugs beyond control of AAPD-induced weight gain.
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 Thr(172) and Ser(485/491) phosphorylation, which indicate activation and inhibition of AMPK, respectively. RESULTS: Body weights were increased by olanzapine in parallel with increased levels of Thr(172) phosphorylation of hypothalamic AMPK. Initially increased rate of weight gain was diminished as Thr(172) 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 Thr(172) phosphorylation and an increase in Ser(485/491) phosphorylation levels. However, in the later stage when no more increases in Thr(172) phosphorylation and weight gain by olanzapine were observed, ALA's action was only indicated by increased levels of Ser(485/491) phosphorylation. CONCLUSIONS: Our data suggest that anti-obesity effects of ALA may be related to modulation of both Ser(485/491) phosphorylation and Thr(172) phosphorylation of hypothalamic AMPK, while olanzapine-induced weight gain may be only associated with increase in Thr(172) phosphorylation. This might be an important mechanistic clue for the future development of anti-obesity drugs beyond control of AAPD-induced weight gain.
Authors: Yossi Dagon; Elizabeth Hur; Bin Zheng; Kerry Wellenstein; Lewis C Cantley; Barbara B Kahn Journal: Cell Metab Date: 2012-06-21 Impact factor: 27.287
Authors: E M van der Zwaal; M Merkestein; Y K Lam; M A D Brans; M C M Luijendijk; L I H Bok; E R Verheij; S E la Fleur; R A H Adan Journal: Int J Obes (Lond) Date: 2011-05-10 Impact factor: 5.095
Authors: He-Ling Dong; Hong-Yuan Wu; Yu Tang; Yin-Wei Huang; Rui-Zhang Lin; Jun Zhao; Xiao-Yang Xu Journal: Nan Fang Yi Ke Da Xue Xue Bao Date: 2018-06-20
Authors: Magdalena Dudek; Kamil Kuder; Marcin Kołaczkowski; Adrian Olczyk; Elżbieta Żmudzka; Aleksandra Rak; Marek Bednarski; Karolina Pytka; Jacek Sapa; Katarzyna Kieć-Kononowicz Journal: Metab Brain Dis Date: 2016-05-24 Impact factor: 3.584