title: Phosphorylation of hypothalamic AMPK on serine(485/491) related to sustained weight loss by alpha-lipoic acid in mice treated with olanzapine.
abstract: BACKGROUND
  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.affiliation: Department of Psychiatry, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors.forename: Hyunjeong
authors.initials: H
authors.lastname: Kim
authors.forename: Minsun
authors.initials: M
authors.lastname: Park
authors.forename: Su-Kyoung
authors.initials: SK
authors.lastname: Lee
authors.forename: Jihyeon
authors.initials: J
authors.lastname: Jeong
authors.forename: Kee
authors.initials: K
authors.lastname: Namkoong
authors.forename: Hyun-Sang
authors.initials: HS
authors.lastname: Cho
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Park
authors.forename: Byung-In
authors.initials: BI
authors.lastname: Lee
authors.forename: Eosu
authors.initials: E
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D000077152:Olanzapine; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000494:pharmacology; D008063:Thioctic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D015430:Weight Gain / Q000187:drug effects*; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D019440:Anti-Obesity Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D012694:Serine; D008063:Thioctic Acid; D055372:AMP-Activated Protein Kinases; D000077152:Olanzapine
references.citation: PLoS One. 2009 Dec 15;4(12):e8322
references.pmid: 20020036
references.citation: Am J Med. 2005 Apr;118 Suppl 2:15S-22S
references.pmid: 15903291
references.citation: Cell Metab. 2012 Jul 3;16(1):104-12
references.pmid: 22727014
references.citation: Nature. 2004 Apr 1;428(6982):569-74
references.pmid: 15058305
references.citation: J Neuroendocrinol. 2011 Mar;23(3):269-81
references.pmid: 21175899
references.citation: N Engl J Med. 2005 Nov 17;353(20):2121-34
references.pmid: 16291982
references.citation: Schizophr Res. 2009 Jun;111(1-3):9-16
references.pmid: 19398192
references.citation: Psychopharmacology (Berl). 2005 Aug;181(1):80-9
references.pmid: 15778884
references.citation: Neuro Endocrinol Lett. 2012;33(5):493-8
references.pmid: 23090266
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3456-9
references.pmid: 17360666
references.citation: Brain Res. 2013 Apr 10;1505:68-74
references.pmid: 23415934
references.citation: Schizophr Bull. 2008 Nov;34(6):1189-99
references.pmid: 18165262
references.citation: Nat Med. 2004 Jul;10(7):727-33
references.pmid: 15195087
references.citation: J Psychopharmacol. 2006 Jan;20(1):75-9
references.pmid: 16204328
references.citation: Int J Obes (Lond). 2012 Feb;36(2):254-61
references.pmid: 21556042
references.citation: Diabetes Educ. 2007 Jan-Feb;33(1):111-7
references.pmid: 17272797
references.citation: PLoS One. 2011;6(6):e20571
references.pmid: 21695181
references.citation: Regul Toxicol Pharmacol. 2006 Oct;46(1):29-41
references.pmid: 16904799
references.citation: Annu Rev Med. 2001;52:503-17
references.pmid: 11160792
references.citation: Neuropsychopharmacology. 1998 Nov;19(5):428-33
references.pmid: 9778664
references.citation: Exp Neurol. 2008 Dec;214(2):276-84
references.pmid: 18809400
references.citation: Diabetologia. 2012 Jun;55(6):1824-35
references.pmid: 22456698
references.citation: J Clin Psychopharmacol. 2008 Apr;28(2):138-46
references.pmid: 18344723
references.citation: Psychopharmacology (Berl). 2012 May;221(1):155-69
references.pmid: 22234378
references.citation: Diabetologia. 1995 Dec;38(12):1425-33
references.pmid: 8786016
references.citation: Lancet. 2013 Sep 14;382(9896):951-62
references.pmid: 23810019
references.citation: Diabetes. 1996 Aug;45(8):1024-9
references.pmid: 8690147
references.citation: Br J Psychiatry Suppl. 2004 Apr;47:S76-9
references.pmid: 15056598
references.citation: Trends Mol Med. 2011 Feb;17(2):97-107
references.pmid: 21185230
references.citation: Cell Mol Neurobiol. 2011 Oct;31(7):985-9
references.pmid: 21681559
references.citation: Vitam Horm. 2008;77:121-48
references.pmid: 17983855
references.citation: Int J Neuropsychopharmacol. 2014 Jan;17(1):91-104
references.pmid: 23919889
references.citation: J Psychopharmacol. 2012 Sep;26(9):1244-51
references.pmid: 22723540
references.citation: J Biol Chem. 2001 Oct 19;276(42):38329-36
references.pmid: 11477096
references.citation: Psychiatry Res. 2001 Apr 15;101(3):277-88
references.pmid: 11311931
references.citation: PLoS One. 2013;8(4):e60722
references.pmid: 23565271
references.citation: J Psychopharmacol. 2011 May;25(5):630-8
references.pmid: 20498135
references.citation: Am J Psychiatry. 2000 Dec;157(12):2057-8
references.pmid: 11097984
references.citation: Int J Neuropsychopharmacol. 2012 Aug;15(7):907-17
references.pmid: 21733226
references.citation: Int J Obes (Lond). 2010 Jun;34(6):970-9
references.pmid: 20065957
references.citation: J Biol Chem. 2005 Jul 1;280(26):25196-201
references.pmid: 15899896
references.citation: Psychoneuroendocrinology. 2005 Jan;30(1):106-10
references.pmid: 15358448
references.citation: FASEB J. 1999 Feb;13(2):411-8
references.pmid: 9973329
references.citation: Int Clin Psychopharmacol. 2002 Jul;17(4):145-60
references.pmid: 12131598
references.citation: Int J Obes (Lond). 2005 Jun;29(6):607-14
references.pmid: 15795750
references.citation: Psychopharmacology (Berl). 2006 Jul;186(4):561-71
references.pmid: 16758241
references.citation: Cell Metab. 2005 Jan;1(1):15-25
references.pmid: 16054041