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Phosphorylation of hypothalamic AMPK on serine(485/491) related to sustained weight loss by alpha-lipoic acid in mice treated with olanzapine.

 Hyunjeong Kim  ;  Minsun Park  ;  Su Kyoung Lee  ;  Jihyeon Jeong  ;  Kee Namkoong  ;  Hyun Sang Cho  ;  Jin Young Park  ;  Byung In Lee  ;  Eosu Kim 
 PSYCHOPHARMACOLOGY, Vol.231(20) : 4059-4069, 2014 
Journal Title
Issue Date
AMP-Activated Protein Kinases/metabolism* ; Animals ; Anti-Obesity Agents/pharmacology ; Antipsychotic Agents/pharmacology* ; Benzodiazepines/pharmacology* ; Body Weight/drug effects ; Eating/drug effects ; Female ; Hypothalamus/drug effects ; Hypothalamus/metabolism* ; Mice ; Obesity/drug therapy ; Obesity/metabolism ; Phosphorylation/drug effects ; Serine/pharmacology ; Thioctic Acid/pharmacology* ; Thioctic Acid/therapeutic use ; Weight Gain/drug effects* ; Weight Loss/drug effects*
Olanzapine ; Alpha-lipoic acid ; AMPK ; Antipsychotics ; Obesity ; Leptin ; Ghrelin
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.
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5. Research Institutes (연구소) > Institute of Behavioral Sciences in Medicine (의학행동과학연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Psychiatry (정신과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
Yonsei Authors
Kim, Eosu(김어수) ORCID logo https://orcid.org/0000-0001-9472-9465
Kim, Hyun Jeong(김현정)
Namkoong, Kee(남궁기) ORCID logo https://orcid.org/0000-0003-1400-8057
Park, Min Sun(박민선)
Park, Jin Young(박진영) ORCID logo https://orcid.org/0000-0002-5351-9549
Lee, Byung In(이병인)
Lee, Su Kyoung(이수경)
Jeong, Jihyeon(정지현)
Cho, Hyun Sang(조현상) ORCID logo https://orcid.org/0000-0003-1019-9941
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